Bicyclic heterocycles as cannabinoid-1 receptor modulators

ABSTRACT

The present application describes compounds according to Formula I, pharmaceutical compositions comprising at least one compound according to Formula I and optionally one or more additional therapeutic agents and methods of treatment using the compounds according to Formula I both alone and in combination with one or more additional therapeutic agents. The compounds have the following general formula:  
                 
 
including all prodrugs, solvates, pharmaceutically acceptable salts and stereoisomers, wherein A, B, R 1 , R 2 , R 3  and R 8  are described herein.

RELATED APPLICATION

This application claims priority benefit under Title 35 § 119(e) of U.S.Provisional Application No. 60/692,045, filed Jun. 17, 2005, thecontents of which are herein incorporated by reference.

BACKGROUND

Delta-9-tetrahydrocannabinol or Delta-9 THC, the principle activecomponent of Cannabis sativa (marijuana), is a member of a large familyof lipophilic compounds (i.e., cannabinoids) that mediate physiologicaland psychotropic effects including regulation of appetite,immunosuppression, analgesia, inflammation, emesis, anti-nocioception,sedation, and intraocular pressure. Other members of the cannabinoidfamily include the endogenous (arachidonic acid-derived) ligands,anandamide, 2-arachidonyl glycerol, and 2-arachidonyl glycerol ether.Cannabinoids work through selective binding to and activation ofG-protein coupled cannabinoid receptors. Two types of cannabinoidreceptors have been cloned including CB-1 (L. A. Matsuda, et al.,Nature, 346, 561-564 (1990)), and CB-2 (S. Munro, et al., Nature, 365,61-65 (1993)). The CB-1 receptor is highly expressed in the central andperipheral nervous systems (M. Glass, et al., Neuroscience, 77, 299-318(1997)), while the CB-2 receptor is highly expressed in immune tissue,particularly in spleen and tonsils. The CB-2 receptor is also expressedon other immune system cells, such as lymphoid cells (S. Galiegue, etal., Eur J Biochem, 232, 54-61 (1995)). Agonist activation ofcannabinoid receptors results in inhibition of cAMP accumulation,stimulation of MAP kinase activity, and closure of calcium channels.

There exists substantial evidence that cannabinoids regulate appetitivebehavior. Stimulation of CB-1 activity by anandamide or Delta-9 THCresults in increased food intake and weight gain in multiple speciesincluding humans (Williams and Kirkham, Psychopharm., 143, 315-317(1999)). Genetic knock-out of CB-1 result in mice that were hypophagicand lean relative to wild-type litter mates (DiMarzo, et al., Nature,410, 822-825 (2001)). Published studies with CB-1 small moleculeantagonists have demonstrated decreased food intake and body weight inrats (Trillou, et. al., Am. J. Physiol. Regul. Integr. Comp. Physiol.,R345-R353, (2003)). Chronic administration of the CB-1 antagonist AM-251for two weeks resulted in substantial body weight reduction anddecreased adipose tissue mass (Hildebrandt, et. al., Eur. J. Pharm, 462,125-132 (2003)). There are multiple studies that have assessed theanorexic effect of the Sanofi CB-1 antagonist, SR-141716 (Rowland, et.al., Pyschopharm., 159, 111-116 (2001); Colombo, et. al., Life Sci., 63,113-117 (1998)). There are at least two CB-1 antagonists in clinicaltrials for regulation of appetite, Sanofi's SR-141716 and Solvay'sSLV-319. Published Phase lib data reveal that SR-141716 dose-dependentlyreduced body weight in human subjects over a 16 week trial period. CB-1antagonists have also been shown to promote cessation of smokingbehavior. Phase II clinical data on smoking cessation were presented inSeptember of 2002 at Sanofi-Synthelabo's Information meeting. This datashowed that 30.2% of patients treated with the highest dose of SR-141716stayed abstinent from cigarette smoke relative to 14.8% for placebo.

DETAILED DESCRIPTION

The present application describes compounds according to Formula I,pharmaceutical compositions comprising at least one compound accordingto Formula I and optionally one or more additional therapeutic agentsand methods of treatment using the compounds according to Formula I bothalone and in combination with one or more additional therapeutic agents.The compounds have the general Formula I

including all prodrugs, solvates, pharmaceutically acceptable salts andstereoisomers, wherein A, B, R¹, R², R³ and R⁸ are described herein.

DEFINITIONS

The following definitions apply to the terms as used throughout thisspecification, unless otherwise limited in specific instances.

As used herein, the term “alkyl” denotes branched or unbranchedhydrocarbon chains containing 1 to 20 carbons, preferably 1 to 12carbons, and more preferably 1 to 8 carbons, in the normal chain, suchas, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl,pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl,2,2,4-trimethylpentyl and the like. Further, alkyl groups, as definedherein, may optionally be substituted on any available carbon atom withone or more functional groups commonly attached to such chains, such as,but not limited to hydroxyl, halo, haloalkyl, mercapto or thio, cyano,alkylthio, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxyl,carbalkoyl, carbonyl, alkenyl, alkynyl, nitro, amino, alkoxy, aryloxy,arylalkyloxy, heteroaryloxy, amido, —OC(O)NRR, —OC(O)R, —OPO₃H, —OSO₃H,and the like to form alkyl groups such as trifluoromethyl,3-hydroxyhexyl, 2-carboxypropyl, 2-fluoroethyl, carboxymethyl,cyanobutyl and the like.

Unless otherwise indicated, the term “alkenyl” as used herein by itselfor as part of another group refers to straight or branched chains of 2to 20 carbons, preferably 2 to 12 carbons, and more preferably 2 to 8carbons with one or more double bonds in the normal chain, such asvinyl, 2-propenyl, 3-butenyl, 2-butenyl, 4-pentenyl, 3-pentenyl,2-hexenyl, 3-hexenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 3-octenyl,3-nonenyl, 4-decenyl, 3-undecenyl, 4-dodecenyl, 4,8,12-tetradecatrienyl,and the like. Further, alkenyl groups, as defined herein, may optionallybe substituted on any available carbon atom with one or more functionalgroups commonly attached to such chains, such as, but not limited tohalo, haloalkyl, alkyl, alkoxy, alkynyl, aryl, arylalkyl, cycloalkyl,amino, hydroxyl, heteroaryl, cycloheteroalkyl, alkanoylamino,alkylamido, arylcarbonylamino, nitro, cyano, thiol, alkylthio and/or anyof the alkyl substituents set out herein.

Unless otherwise indicated, the term “alkynyl” as used herein by itselfor as part of another group refers to straight or branched chains of 2to 20 carbons, preferably 2 to 12 carbons and more preferably 2 to 8carbons with one or more triple bonds in the normal chain, such as2-propynyl, 3-butynyl, 2-butynyl, 4-pentynyl, 3-pentynyl, 2-hexynyl,3-hexynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 3-octynyl, 3-nonynyl,4-decynyl, 3-undecynyl, 4-dodecynyl and the like. Further, alkynylgroups, as defined herein, may optionally be substituted on anyavailable carbon atom with one or more functional groups commonlyattached to such chains, such as, but not limited to halo, haloalkyl,alkyl, alkoxy, alkenyl, aryl, arylalkyl, cycloalkyl, amino, hydroxyl,heteroaiyl, cycloheteroalkyl, alkanoylamino, alkylamido,arylcarbonylamino, nitro, cyano, thiol, alkylthio and/or any of thealkyl substituents set out herein.

Unless otherwise indicated, the term “cycloalkyl” as employed hereinalone or as part of another group includes saturated or partiallyunsaturated (containing one or more double bonds) cyclic hydrocarbongroups containing 1 to 3 rings, appended or fused, includingmonocyclicalkyl, bicyclicalkyl and tricyclicalkyl, containing a total of3 to 20 carbons forming the rings, preferably 3 to 10 carbons, formingthe ring and which may be fused to 1 or 2 aromatic rings as describedfor aryl, which include cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl and cyclododecyl,cyclohexenyl,

Further, any cycloalkyl may be optionally substituted through anyavailable carbon atoms with one or more groups selected from hydrogen,halo, haloalkyl, alkyl, alkoxy, haloalkyloxy, hydroxyl, alkenyl,alkynyl, aryl, aryloxy, heteroaryl, heteroaryloxy, arylalkyl,heteroarylalkyl, alkylamido, alkanoylamino, oxo, acyl,arylcarbonylamino, amino, nitro, cyano, thiol and/or alkylthio and/orany of the alkyl substituents.

The term “cycloalkylalkyl” as used herein alone or as part of anothergroup refers to alkyl groups as defined above having a cycloalkylsubstituent, wherein said “cycloalkyl” and/or “alkyl” groups mayoptionally be substituted as defmed above.

Unless otherwise indicated, the term “aryl” as employed herein alone oras part of another group refers to monocyclic and bicyclic aromaticgroups containing 6 to 10 carbons in the ring portion (such as phenyl ornaphthyl including 1-naphthyl and 2-naphthyl) and may optionally includeone to three additional rings fused to a carbocyclic ring or aheterocyclic ring, for example,

Further, “aryl”, as defined herein, may optionally be substituted withone or more functional groups, such as halo, alkyl, haloalkyl, alkoxy,haloalkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl,heterocycloalkyl, aryl, heteroaryl, arylalkyl, aryloxy, aryloxyalkyl,arylalkoxy, alkoxycarbonyl, arylcarbonyl, arylalkenyl,aminocarbonylaryl, arylthio, arylsulfinyl, arylazo, heteroarylalkyl,heteroarylalkenyl, heteroarylheteroaryl, heteroaryloxy, hydroxyl, nitro,cyano, amino, substituted amino wherein the amino includes 1 or 2substituents (which are alkyl, aryl or any of the other aryl compoundsmentioned in the definitions), thiol, alkylthio, arylthio,heteroarylthio, arylthioalkyl, alkoxyarylthio, alkylcarbonyl,arylcarbonyl, alkylaminocarbonyl, arylaminocarbonyl, alkoxycarbonyl,aminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy, alkylcarbonylamino,arylcarbonylamino, arylsulfinyl, arylsulfinylalkyl, arylsulfonylamino orarylsulfonaminocarbonyl and/or any of the alkyl substituents set outherein.

Unless otherwise indicated, the term “heteroaryl” as used herein aloneor as part of another group refers to a 5- or 6-membered aromatic ringwhich includes 1, 2, 3 or 4 hetero atoms such as nitrogen, oxygen orsulfur. Such rings may be fused to an aryl, cycloalkyl, heteroaryl orheterocyclyl and include possible N-oxides as described in Katritzky, A.R. and Rees, C. W., eds. Comprehensive Heterocyclic Chemistry: TheStructure, Reactions, Synthesis and Uses of Heterocyclic Compounds 1984,Pergamon Press, New York, N.Y.; and Katritzky, A. R., Rees, C. W.,Scriven, E. F., eds. Comprehensive Heterocyclic Chemistry II: A Reviewof the Literature 1982- 1995 1996, Elsevier Science, Inc., Tarrytown,N.Y.; and references therein. Further, “heteroaryl”, as defined herein,may optionally be substituted with one or more substituents such as thesubstituents included above in the definition of “substituted alkyl” and“substituted aryl”. Examples of heteroaryl groups include the following:

and the like.

The term “heteroarylalkyl” as used herein alone or as part of anothergroup refers to alkyl groups as defined above having a heteroarylsubstituent, wherein said heteroaryl and/or alkyl groups may optionallybe substituted as defined above.

The term “heterocyclo”, “heterocycle”, “heterocyclyl” or “heterocyclicring”, as used herein, represents an unsubstituted or substituted stable4 to 7-membered monocyclic ring system which may be saturated orunsaturated, and which consists of carbon atoms, with one to fourheteroatoms selected from nitrogen, oxygen or sulfur, and wherein thenitrogen and sulfur heteroatoms may optionally be oxidized, and thenitrogen heteroatom may optionally be quaternized. The heterocyclic ringmay be attached at any heteroatom or carbon atom which results in thecreation of a stable structure. Examples of such heterocyclic groupsinclude, but is not limited to, azetidinyl, pyrrolidinyl, piperidinyl,piperazinyl, oxopiperazinyl, oxopiperidinyl, oxopyrrolidinyl,oxoazepinyl, azepinyl, pyrrolyl, pyrrolidinyl, furanyl, thienyl,pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl,pyridyl, pyrazinyl, pyrmidinyl, pyridazinyl, oxazolyl, oxazolidinyl,isooxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl,isothiazolyl, thiadiazolyl, tetrahydropyranyl, thiamorpholinyl,thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, oxadiazolyl andother heterocycles described in Katritzky, A. R. and Rees, C. W., eds.Comprehensive Heterocyclic Chemistry: The Structure, Reactions,Synthesis and Uses ofHeterocyclic Compounds 1984, Pergamon Press, NewYork, N.Y.; and Katritzky, A. R., Rees, C. W., Scriven, E. F., eds.Comprehensive Heterocyclic Chemistry II: A Review of the Literature1982-1995 1996, Elsevier Science, Inc., Tarrytown, N.Y.; and referencestherein.

The term “heterocycloalkyl” as used herein alone or as part of anothergroup refers to alkyl groups as defined above having a heterocyclylsubstituent, wherein said heterocyclyl and/or alkyl groups mayoptionally be substituted as defined above.

The terms “arylalkyl”, “arylalkenyl” and “arylalkynyl” as used alone oras part of another group refer to alkyl, alkenyl and alkynyl groups asdescribed above having an aryl substituent. Representative examples ofarylalkyl include, but are not limited to, benzyl, 2-phenylethyl,3-phenylpropyl, phenethyl, benzhydryl and naphthylmethyl and the like.

The term “alkoxy”, “aryloxy”, “heteroaryloxy” “arylalkyloxy”, or“heteroarylalkyloxy” as employed herein alone or as part of anothergroup includes an alkyl or aryl group as defined above linked through anoxygen atom.

The term “halogen” or “halo” as used herein alone or as part of anothergroup refers to chlorine, bromine, fluorine, and iodine, with bromine,chlorine or fluorine being preferred.

The term “cyano,” as used herein, refers to a —CN group.

The term “methylene,” as used herein, refers to a —CH₂— group.

The term “nitro,” as used herein, refers to a —NO₂ group.

The compounds of formula I can be present as salts, which are alsowithin the scope of this invention. Pharmaceutically acceptable (i.e.,non-toxic, physiologically acceptable) salts are preferred. If thecompounds of formula I have, for example, at least one basic center,they can form acid addition salts. These are formed, for example, withstrong inorganic acids, such as mineral acids, for example sulfuricacid, phosphoric acid or a hydrohalic acid, with organic carboxylicacids, such as alkanecarboxylic acids of 1 to 4 carbon atoms, forexample acetic acid, which are unsubstituted or substituted, forexample, by halogen as chloroacetic acid, such as saturated orunsaturated dicarboxylic acids, for example oxalic, malonic, succinic,maleic, fumaric, phthalic or terephthalic acid, such ashydroxycarboxylic acids, for example ascorbic, glycolic, lactic, malic,tartaric or citric acid, such as amino acids, (for example aspartic orglutamic acid or lysine or arginine), or benzoic acid, or with organicsulfonic acids, such as (C₁-C₄) alkyl or arylsulfonic acids which areunsubstituted or substituted, for example by halogen, for examplemethyl- or p-toluene-sulfonic acid. Corresponding acid addition saltscan also be formed having, if desired, an additionally present basiccenter. The compounds of formula I having at least one acid group (forexample COOH) can also form salts with bases. Suitable salts with basesare, for example, metal salts, such as alkali metal or alkaline earthmetal salts, for example sodium, potassium or magnesium salts, or saltswith ammonia or an organic amine, such as morpholine, thiomorpholine,piperidine, pyrrolidine, a mono, di or tri-lower alkylamine, for exampleethyl, tert-butyl, diethyl, diisopropyl, triethyl, tributyl ordimethyl-propylamine, or a mono, di or trihydroxy lower alkylamine, forexample mono, di or triethanolamine. Corresponding internal salts mayfurthermore be formed. Salts which are unsuitable for pharmaceuticaluses but which can be employed, for example, for the isolation orpurification of free compounds of formula I or their pharmaceuticallyacceptable salts, are also included.

Preferred salts of the compounds of formula I which contain a basicgroup include monohydrochloride, hydrogensulfate, methanesulfonate,phosphate, nitrate or acetate.

Preferred salts of the compounds of formula I which contain an acidgroup include sodium, potassium and magnesium salts and pharmaceuticallyacceptable organic amines.

The term “modulator” refers to a chemical compound with capacity toeither enhance (e.g., “agonist” activity) or partially enhance (e.g.,“partial agonist” activity) or inhibit (e.g., “antagonist” activity or“inverse agonist” activity) a finctional property of biological activityor process (e.g., enzyme activity or receptor binding); such enhancementor inhibition may be contingent on the occurrence of a specific event,such as activation of a signal transduction pathway, and/or may bemanifest only in particular cell types.

The term “bioactive metabolite” as employed herein refers to anyfunctional group contained in a compound of formula I with an openvalence for further substitution wherein such substitution can, uponbiotransformation, generate a compound of formula I. Examples of suchfunctional groups of bioactive metabolites include, but are not limitedto, —OH, —NH or functional groups wherein the hydrogen can be replacedwith a finctional group such as —PO₃H₂ for example, which, uponbiotransformation generates an —OH or —NH finctional group of a compoundof formula I.

The term “prodrug esters” as employed herein includes esters andcarbonates formed by reacting one or more hydroxyls of compounds offormula I with alkyl, alkoxy, or aryl substituted acylating agentsemploying procedures known to those skilled in the art to generateacetates, pivalates, methylcarbonates, benzoates and the like. Prodrugesters may also include—but are not limited to groups such as phosphateesters, phosphonate esters, phosphonamidate esters, sulfate esters,sulfonate esters, and sulfonamidate esters wherein the ester may befurther substituted with groups that confer a pharmaceutical advantagesuch as—but not limited to—favorable aqueous solubility or in vivoexposure to the bioactive component formula I.

The term “prodrug” as employed herein includes finctionalization ofbioactive amine- or hydroxyl-containing compounds of formula I to formalkyl-, acyl-, sulfonyl-, phosphoryl-, or carbohydrate-substitutedderivatives. Such derivatives are formed by reacting compounds offormula I with alkylating-, acylating-, sulfonylating-, orphosphorylating reagents employing procedures known to those skilled inthe art. Alkylation of amines of formula I may result in—but are notlimited to—derivatives that include spacer units to other prodrugmoieties such as substituted alkyoxymethyl-, acyloxymethyl-,phosphoryloxymethyl-, or sulfonyloxymethyl-groups. Alkylation of aminesof formula I may result in the generation of quarternary amine saltsthat act in vivo to provide the bioactive agent (i.e., the compound offormula I).

Preferred prodrugs consist of a compound of formula I where a pendanthydroxyl is phosphorylated to generate a phosphate derivative. Such aprodrug may also include a spacer group between the compound of formulaI and the phosphate group, such as a methyleneoxy-group. Methods togenerate such a prodrug from a compound of formula I are known to thoseskilled in the art, and are listed in the references below.

Preferred prodrugs also consist of a compound of formula I where apendant amine, such as a pyridine group, is alkylated with a group, suchas methyl, to form a quarternary ammonium ion salt. Methods to generatesuch a prodrug from a compound of formula I are known to those skilledin the art, and are listed in the references below.

Any compound that can be converted in vivo to provide the bioactiveagent (i.e., the compound of formula I) is a prodrug within the scopeand spirit of the invention.

Various forms of prodrugs are well known in the art. A comprehensivedescription of prodrugs and prodrug derivatives are described in:

a) The Practice of Medicinal Chemistry, Camille G. Wermuth et al., Ch31, (Academic Press, 1996);

b) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985);

c) A Textbook of Drug Design and Development, P. Krogsgaard-Larson andH. Bundgaard, eds. Ch 5, pgs 113-191 (Harwood Academic Publishers,1991);

d) Hydrolysis in Drug and Prodrug Metabolism, B. Testa and J. M. Mayer,(Verlag Helvetica Chimica Acta AG, Zurich, Switzerland; Wiley-VCH,Weinheim, Federal Republic of Germany, 2003);

e) Ettmayer, P.; Amidon, G. L.; Clement, B.; Testa, B. “Lessons Learnedfrom Marketed and Investigational Prodrugs” J. Med. Chem. 2004, 47 (10),2393-2404; and

f) Davidsen, S. K. et al. “N-(Acyloxyalkyl)pyridinium Salts as SolubleProdrugs of a Potent Platelet Activating Factor Antagonist” J Med. Chem.1994, 37 (26), 4423-4429.

Said references are incorporated herein by reference.

An administration of a therapeutic agent of the invention includesadministration of a therapeutically effective amount of the agent of theinvention. The term “therapeutically effective amount” as used hereinrefers to an amount of a therapeutic agent to treat or prevent acondition treatable by administration of a composition of the invention.That amount is the amount sufficient to exhibit a detectable therapeuticor preventative or ameliorative effect. The effect may include, forexample, treatment or prevention of the conditions listed herein. Theprecise effective amount for a subject will depend upon the subject'ssize and health, the nature and extent of the condition being treated,recommendations of the treating physician, and the therapeutics orcombination of therapeutics selected for administration.

All stereoisomers of the compounds of the instant invention arecontemplated, either in mixture or in pure or substantially pure form.The compounds of the present invention can have asymmetric centers atany of the carbon atoms including any one of the R substituents.Consequently, compounds of formula I can exist in enantiomeric ordiastereomeric forms or in mixtures thereof. The processes forpreparation can utilize racemates, enantiomers or diastereomers asstarting materials. When diastereomeric or enantiomeric products areprepared, they can be separated by conventional methods for example,chromatographic techniques, chiral HPLC or fractional crystallization.

The compounds of formula I of the invention can be prepared as shown inthe following reaction schemes and description thereof, as well asrelevant published literature procedures that may be used by one skilledin the art. Exemplary reagents and procedures for these reactions appearhereinafter and in the working Examples.

ABBREVIATIONS

The following abbreviations are employed in the Schemes, Examples andelsewhere herein:

-   AcOH=acetic acid-   AlCl₃=aluminum chloride-   Boc=tert-butoxycarbonyl-   DMF=N,N-dimethylformamide-   DMSO=dimethyl sulfoxide-   EDAC=N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride-   EtOAc=ethyl acetate-   Et₃N=triethylamine-   Et₂O=diethyl ether-   HPLC or LC=high performance liquid chromatography-   HOBt=1-hydroxybenzotriazole-   (i-Pr)₂EtN=diisopropylethylamine-   K₃PO₄=potassium phosphate tribasic-   K₂CO₃=potassium carbonate-   MeOH=methanol-   MOM=methoxymethyl-   Ms=methanesulfonyl-   MS or Mass Spec=mass spectrometry-   NaCl=sodium chloride-   NaHCO₃=sodium bicarbonate-   Na₂SO₄=sodium sulfate-   Na₂CO₃=sodium carbonate-   NaOH sodium hydroxide-   Pd(Ph₃P)₄=tetrakis(triphenylphosphine)palladium(0)-   Ph₃PCl₂=triphenylphosphine dichloride-   PG=protecting group-   POCl₃=phosphorus oxychloride-   Pd(dppf)Cl₂=[1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium(II)-   TFA=trifluoroacetic acid-   THF=tetrahydrofuran-   Ts=p-toluenesulfonyl-   min=minute(s)-   h=hour(s)-   L=liter(s)-   mL=milliliter(s)-   μL=microliter(s)-   g=gram(s)-   mg=milligram(s)-   mol=moles-   mmol=millimole(s)-   M=molar-   nM=nanomolar-   [M+H]⁺=parent plus a proton-   [M+Na]⁺=parent plus a sodium ion-   [M−H]⁻=parent minus a proton

Compounds of the present invention may be prepared by proceduresillustrated in the accompanying schemes.

Methods Of Preparation

The compounds of the present invention may be prepared by methods suchas those illustrated in the following Schemes. Solvents, temperatures,pressures, and other reaction conditions may readily be selected by oneof ordinary skill in the art. Starting materials are commerciallyavailable or can be readily prepared by one of ordinary skill in the artusing known methods. For all of the schemes and compounds describedbelow, A, B, R¹, R², R³ and R⁸ are as described for a compound offormula I.

The following are the definitions of symbols used throughout Schemes 1to 3:

-   -   PG suitable nitrogen or oxygen protecting group, exemplified by        benzyl, methoxymethyl-[MOM], benzyloxymethyl-[BOM],        2-(trimethylsilyl)ethoxymethyl-[SEM], methoxyethoxymethyl-[MEM],        or t-butyl groups;    -   EE leaving group exemplified by halogen (F, Cl, Br, I) and        sulfonates (—OSO₂-aryl (e.g., —OSO₂Ph or —OSO₂PhCH₃), or        —OSO₂-alkyl (e.g., —OSO₂CH₃ or —OSO₂CF₃).        Compounds of formula II are either commercially available or        available by means known to one skilled in the art. Compounds of        formula III can be prepared by reacting compounds of formula II        with an appropriately protected hydrazine such as        benzylhydrazine. Exemplary nitrogen protecting groups and        methods of protecting the nitrogen are similar to those for        protecting amines, such as those described in T. W. Greene        and P. G. M. Wuts, Protecting Groups in Organic Synthesis, John        Wiley & Sons, Inc, New York, 1991. Preferred nitrogen protecting        groups are benzyl, tert-butyl, methoxymethyl (MOM) groups.

Compounds of formula IV, where EE¹=Cl, can be prepared by reactingcompounds of formula III with a chlorinating agent such as POCl₃, eitherneat or in an inert solvent such as toluene at elevated temperature.

Compounds of formula V can be prepared by reaction of compounds offormula IV with an activated R¹, such as an activated boronic acid, tin,Grignard reagents, Zinc, Cu, etc in the presence of an appropriatecatalyst if needed such as Pd(dppf)Cl₂, complex with CH₂Cl₂.

Compounds of formula VI can be prepared by removing the protecting group(PG) in compound V under catalytic hydrogenation (for benzyl), or Lewisacid (e.g. AlCl₃ for benzyl or MOM), acidic (e.g. TFA for t-butyl orBoc-) conditions.

Compounds of formula VII, where EE⁵=Cl, can be prepared by reactingcompounds of formula VI with a chlorinating agent such as POCl₃, eitherneat or in an inert solvent such as toluene at elevated temperature.Compounds of formula VII, where EE⁵=Cl, can also be prepared accordingto the procedures described in Toma, L.; et. al. Heterocycles, 57(1),pp. 39-46, (2002).

Compounds of formula VIII can be prepared by reacting compounds offormula VII with hydrazine in an inert solvent such as pyridine atelevated temperature.

Compounds of formula IX can be prepared by reacting compounds of formulaVIII with a carbonylating agent such as carbonyldiimidazole, phosgene,triphosgene or urea in an inert solvent such as tetrahydrofuran.

Compounds of formula X, where be EE=Cl, can be prepared by reactingcompounds of formula IX with a chlorinating agent such as POCl₃, eitherneat or in an inert solvent such as toluene at elevated temperature.

Compounds of formula XI can be prepared by reacting compounds of formulaVIII with a carboxylic acid (R⁸—B—CO₂H, where B is CR⁶R⁷) via amide bondformation which employs either a coupling reagent, such as 1(3-30dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, or a mixedanhydride formed between the carboxylic acid and isobutyl chloroformatein the presence of a base, such as triethylamine.

Compounds of formula Ia can be prepared from a compound of formula X viadisplacement of the leaving group (EE) by the conjugate base of acompound R⁸—B—H (where B is O or NR⁶) in an inert solvent, such as THFin the presence of a base.

Exemplary bases include triethylamine, sodium carbonate, potassiumcarbonate, cesium carbonate, sodium hydride, sodium alkoxide, potassiumtert-butoxide, or alkyl lithiums.

Compounds of formula Ia (where B is CR⁶R⁷) can be prepared fromcompounds of formula XI via intramolecular cyclization in the presenceof an activating reagent, such as triphenylphosphine dichloride, oracetic acid in ethanol at elevated temperature.

Compounds of formula XII can be prepared by reacting compounds offormula II with hydrazine dihydrochloride in an aqueous or alcoholicsolvent at elevated temperature.

Compounds of formula XIII, where EE¹=EE⁵=Cl, can be prepared by reactingcompounds of formula XII with a chlorinating agent such as POCl₃, eitherneat or in an inert solvent such as toluene at elevated temperature.

Compounds of formula XIV can be prepared by reacting compounds offormula XIII with hydrazine in an inert solvent such as pyridine atelevated temperature.

Compounds of formula XV can be prepared by reacting compounds of formulaXIV with a carboxylic acid (R⁸—B—CO₂H, where B is CR⁶R⁷) via amide bondformation which employs either a coupling reagent, such as1(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, or a mixedanhydride formed between the carboxylic acid and isobutyl chloroformatein the presence of a base, such as triethylamine.

Compounds of formula XVI can be prepared from compounds of formula XVvia intramolecular cyclization in the presence of an activating reagent,such as triphenylphosphine dichloride, or acetic acid in ethanol atelevated temperature.

Compounds of formula Ia can be prepared by reaction of compounds offormula XVI with an activated R¹, such as an activated boronic acid,tin, Grignard reagents, Zinc, Cu, etc in the presence of an appropriatecatalyst if needed such as Pd(dppf)Cl₂, complex with CH₂Cl₂.

Compounds of formula XVII are either commercially available or can beprepared by procedures analogous to those described in Cottet, F. andSchlosser, M. Tetrahedron, 60, pp. 11896-11874(2004).

Compounds of formula XVIII can be prepared by reaction of compounds offormula XVII with an activated R², such as an activated boronic acid,tin, Grignard reagents, Zinc, Cu, etc in the presence of an appropriatecatalyst if needed such as Pd(Ph₃P)₄.

Compounds of formula XIX can be prepared by reaction of compounds offormula XVIII with an activated R¹, such as an activated boronic acid,tin, Grignard reagents, Zinc, Cu, etc in the presence of an appropriatecatalyst if needed such as Pd₂(dba)₃.

Compounds of formula XX can be prepared by reacting compounds of formulaXIX with hydrazine in an inert solvent, such as pyridine, at elevatedtemperature.

Compounds of formula XXI can be prepared by reacting compounds offormula XX with a carboxylic acid (R⁸—B—CO₂H, where B is CR⁶R⁷) viaamide bond formation reaction which employs either a coupling reagent,such as 1(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, inthe presence of a base, such as diisopropylethylamine.

Compounds of formula Ib can be prepared from compounds of formula XXIvia intramolecular cyclization in the presence of an activating reagent,such as triphenylphosphine dichloride, or acetic acid in ethanol atelevated temperature.

Compounds of formula XXII can be prepared by reacting compounds offormula XX with a carbonylating agent such as carbonyldiimidazole,phosgene, triphosgene or urea in an inert solvent such astetrahydrofuran.

Compounds of formula XXIII, where EE=Cl, can be prepared by reactingcompounds of formula XXII with a chlorinating agent such as POCl₃,either neat or in an inert solvent such as toluene at elevatedtemperature.

Compounds of formula Ib can be prepared from a compound of formula XXIIIvia displacement of the leaving group (EE) by the conjugate base of acompound R⁸—B—H (where B is O or NR⁶) in an inert solvent, such as THFin the presence of a base. Exemplary bases include triethylamine, sodiumcarbonate, potassium carbonate, cesium carbonate, sodium hydride, sodiumalkoxide, potassium tert-butoxide, or alkyl lithiums.

Compounds of formula XXIV can be prepared by reacting compounds offormula XVIII with hydrazine in an inert solvent, such astetrahydrofuran, at elevated temperature.

Compounds of formula XXV can be prepared by reacting compounds offormula XXIV with a carboxylic acid (R⁸—B—CO₂H, where B is CR⁶R⁷) viaamide bond formation reaction which employs either a coupling reagent,such as 1(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, orbromotripyrrolidinophosphonium hexafluorophosphate in the presence of abase, such as diisopropylethylamine.

Compounds of formula XXVI can be prepared from compounds of formula XXVvia intramolecular cyclization in the presence of an activating reagent,such as triphenylphosphine dichloride, or acetic acid in an inertsolvent at elevated temperature.

Compounds of formula Ib can be prepared by reaction of compounds offormula XXVI with an activated R¹, such as an activated boronic acid,tin, Grignard reagents, Zinc, Cu, etc in the presence of an appropriatecatalyst if needed such as Pd(PPh₃)₄.

Compounds of formula XXVIII (where A=N or CR⁴, R=alkyl) can be preparedby reacting compounds of formula XXVII with diethyl oxylate in an inertsolvent, such as toluene, at elevated temperature, or reacting withethyl glyoxylate in tetrahydrofuran first, then with bromine at elevatedtemperature.

Compounds of formula Ic (where A=N or CR⁴) can be prepared by reactionof compounds of formula XXVIII with excess of an amine of formula R⁶R⁹NHeither neat or in a polar solvent, such as methanol or ethanol atelevated temperature.

EXAMPLES

The following examples serve to better illustrate, but not limit, someof the preferred embodiments of the invention.

Analytical HPLC and HPLC/MS Methods Employed in Characterization ofExamples

Analytical HPLC was performed on Shimadzu LC10AS liquid chromatographs.

Analytical HPLC/MS was performed on Shimadzu LC10AS liquidchromatographs and Waters ZMD Mass Spectrometers using the followingmethods:

Method A. Linear gradient of 0 to 100% solvent B over 4.0 min, with 1min hold at 100% B;

-   -   UV visualization at 220 nm    -   Column: Phenomenex Lura C18, 4.6×50 mm    -   Flow rate: 4 ml/min        Solvent A: 0.1% trifluoroacetic acid, 90% water, 10% methanol        Solvent B: 0.1% trifluoroacetic acid, 10% water, 90% methanol.

Method B. Linear gradient of 0 to 100% solvent B over 2.0 min, with 1min hold at 100% B;

-   -   UV visualization at 220 nm    -   Column: Phenomenex Lura C18, 4.6×30 mm    -   Flow rate: 5 ml/min        Solvent A: 0.1% trifluoroacetic acid, 90% water, 10% methanol        Solvent B: 0.1% trifluoroacetic acid, 10% water, 90% methanol.        NMR Employed in Characterization of Examples

¹H NMR spectra were obtained with Bruker or JOEL fourier transformspectrometers operating at the following frequencies: ¹H NMR: 400 MHz(Bruker), 400 MHz (JOEL), or 500 MHz (JOEL); ¹³C NMR: 100 MHz (Bruker),100 MHz (JOEL) or 125 MHz (JOEL). Spectra data are reported as Chemicalshift (multiplicity, number of hydrogens, coupling constants in Hz) andare reported in ppm (δ units) relative to either an internal standard(tetramethylsilane=0 ppm) for ¹H NMR spectra, or are referenced to theresidual solvent peak (2.49 ppm for CD₂HSOCD₃, 3.30 ppm for CD₂HOD, 7.24ppm for CHCl₃, 39.7 ppm for CD₃SOCD₃, 49.0 ppm for CD₃OD, 77.0 ppm forCDCl₃). All ¹³C NMR spectra were proton decoupled.

Example 1 Preparation of6-(2-chlorophenyl)-7-(4-chlorophenyl)-N-cyclohexyl-[1,2,4]triazolo[4,3-b]pyridazin-3-amine

1A. Preparation of2-benzyl-5-(4-chlorophenyl)-6-hydroxypyridazin-3(2H)-one

To a suspension of 3-(4-chlorophenyl)-2,5-furandione (10.24 g, 66.9mmol) in acetic acid (300 mL) was added benzylhydrazine dihydrochloridein one portion (19.6 g, 100 mmol). The reaction mixture was stirred atreflux for 14 h. Analysis by HPLC/MS indicated the reaction wascomplete. After cooling to room temperature, the resulting whitesuspension was filtered. The collected solid was washed with EtOAc (20mL×2), and dried in a 50° C. vacuum oven for 16 h to yield 6.5 g of thedesired product as a white solid. The filtrate was concentrated underreduced pressure, and the obtained residue was crystallized in EtOAc toafford additional 1.6 g of the title compound (8.1 g in total, 39%yield). HPLC/MS (method A): retention time=3.29 min, (M+H)⁺=313.1. ¹HNMR (DMSO-d6, 500 MHz): δ 11.62 (s, 1H), 7.65 (d, J=10 Hz, , 2H), 7.51(d, J=10 Hz, 2H), 7.23-7.38 (m, 5H), 7.04 (s, 1H), 5.11 (s, 2H).

1B. Preparation of2-benzyl-6-chloro-5-(4-chlorophenyl)pyridazin-3(2H)-one

A suspension of 2-benzyl-5-(4-chlorophenyl)-6-hydroxypyridazin-3(2H)-one(8.5 g, 27.2 mmol) in phosphorus oxychloride (50 mL) was stirred at 95°C. for 1 h. Analysis by HPLC/MS indicated the starting material had beenconsumed. After cooling to room temperature, the reaction mixture wasconcentrated under reduced pressure. The obtained residue was dilutedwith EtOAc. The resulting EtOAc solution was washed with saturatedaqueous NaHCO₃, saturated aqueous NaCl, dried (Na₂SO₄), filtered andconcentrated under reduced pressure. The crude product was purifiedusing a silica gel cartridge (330 g) eluting with a gradient of EtOAc(0-40%) in hexanes to afford 6.2 g (69%) of the title compound as awhite solid. HPLC/MS (method A): retention time=3.80 min, (M+H)⁺=331.0.¹H NMR (CDCl₃, 400 MHz): δ7.27-7.80(m, 9H), 6.88 (s, 1H), 5.36 (s, 2H).

1C. Preparation of2-benzyl-6-(2-chlorophenyl)-5-(4-chlorophenyl)pyridazin-3(2H)-one

To a flame-dried round bottom flask was placed2-benzyl-6-chloro-5-(4-chlorophenyl)pyridazin-3(2H)-one (6.0 g, 18.1mmol), 2-chlorophenylboronic acid (5.7 g, 36.2 mmol), K₃PO₄ (7.7 g, 36.2mmol), and [1,1′bis(diphenylphosphino)-ferrocene]dichloropalladium(II),complex with CH₂Cl₂ (1:1) (2.96 g, 3.6 mmol). The flask was purged withargon for 15 min before degassed THF (120 mL) was added. The reactionmixture was stirred in a 70° C. oil bath under argon for 16 h. Aftercooling to room temperature, the reaction mixture was diluted with EtOAc(200 mL), washed with 1N aqueous NaOH (50 mL), H₂O, saturated aqueousNaCl, dried (Na₂SO₄), filtered and concentrated under reduced pressure.The crude product was purified using a silica gel cartridge (330 g)eluting with a gradient of EtOAc (0-40%) in hexanes to afford 6.5 g(88%) of the title compound as a white solid. HPLC/MS (method A):retention time=3.97 min, (M+H)⁺=407.0. ¹H NMR (CDCl₃, 400 MHz): δ7.51(d, 2H, J=8.0 Hz), 7.24-7.40 (m, 9H), 6.95-7.03 (m, 3H), 5.33 (s, 2H).

1D. Preparation of6-(2-chlorophenyl)-5-(4-chlorophenyl)pyridazin-3(2H)-one

To a solution of2-benzyl-6-(2-chlorophenyl)-5-(4-chlorophenyl)pyridazin-3(2h)-one (6.4g, 15.7 mmol) in toluene (100 mL) at 90° C. was added aluminum chloride(5.23 g, 39.3 mmol) in one portion. After addition, the reaction mixturewas stirred at 90° C. for 20 min. After cooling to room temperature, thereaction mixture was concentrated under reduced pressure to reduce thevolume to about 50 mL, then water (150 mL) was added. The resultingmixture was sonicated for 5 min, then stirred at room temperature for 10min. The resulting suspension was filtered, the collected solid waswashed with water (20 mL×3), hexanes (20 mL×3) and dried in a 50° C.vacuum oven for 16 h to afford 4.2 g (76%) of the title compound as awhite solid. HPLC/MS (method A): retention time=3.27 min, (M+H)⁺=317.0.¹H NMR (CDCl₃, 400 MHz): δ11.6 (S, 1H), 7.17-7.40 (m, 6H), 6.90-7,10 (m,3H).

1E. Preparation of6-chloro-3-(2-chlorophenyl)4-(4-chlorophenyl)pyridazine

A suspension of 6-(2-chlorophenyl)-5-(4-chlorophenyl)pyridazin-3(2H)-one(4.1 g, 12.9 mmol) in phosphorus oxychloride (15 mL) was stirred at 95°C. for 1 h. After cooling to room temperature, the reaction mixture wasconcentrated under reduced pressure. The residue was partitioned betweenEtOAc and saturated aqueous NaHCO₃. The separated aqueous layer wasextracted with EtOAc (40 mL×2). The combined organic was washed withsaturated aqueous NaHCO₃, saturated aqueous NaCl, dried (Na₂SO₄) andconcentrated under reduced pressure to afford 4.2 g (97%) of the titlecompound as a pink foam. HPLC/MS (method A): retention time=3.50 min,(M+H)⁺=335.0.

1F. Preparation of1-(6-(2-chlorophenyl)-5-(4-chlorophenyl)pyridazin-3)hydrazine

To a solution of6-chloro-3-(2-chlorophenyl)-4-(4-chlorophenyl)pyridazine (2.1 g, 6.26mmol) in pyridine (20 mL) at 90° C. was added anhydrous hydrazine (1mL), and the resulting mixture was stirred at 90° C. for 1 h. Analysisby HPLC/MS indicated the reaction was not complete. Additional hydrazine(0.5 mL) was added, and the reaction continued at 90° C. for 1 h more.After cooling to room temperature, the reaction was concentrated underreduced pressure. The obtained residue was treated with water (50 mL),and the resulting suspension stirred at room temperature for 10 min,then filtered. The collected solid was washed with water (20 mL×3),dried in a 50° C. vacuum oven for 16 h to afford 2.1 g (100%) of thetitle compound as a pink solid. HPLC/MS (method A): retention time=2.67min, (M+H)⁺=331.0.

1G. Preparation of6-(2-chlorophenyl)-7-(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H1)-one

To a suspension of 1,1′-carbonyl diimidazole (2.84 g, 17.5 mmol) inanhydrous THF (15 mL) at 65° C. was added a suspension of1-(6-(2-chlorophenyl)-5-(4-chlorophenyl)pyridazin-3)hydrazine (1.16 g,3.5 mmol) in THF (20 mL). After addition, the reaction mixture wasstirred at 65° C. for 20 min. Analysis by HPLC/MS indicated the startingmaterial had been consumed. After cooling to room temperature, thereaction was concentrated under reduced pressure. The obtained residuewas dissolved in EtOAc (20 mL), and the resulting solution was adjustedto pH 6-8 by slow addition of iced cooled 1N aqueous HCl. The resultingyellow suspension was filtered. The collected solid was washed withwater (20 mL×2), EtOAc (10 mL×2), and dried in air to obtain 850 mg ofthe title compound as a yellow solid. The filtrate was extracted withEtOAc (20 mL×2). The combined EtOAc extracts were washed with saturatedaqueous NaCl, dried (Na₂SO₄), filtered and concentrated under reducedpressure. The obtained residue was triturated with EtOAc (10 mL), andthe resulting yellow precipitate was collected by filtration. Thecollected solid was washed with EtOAc/hexanes (1:2) (10 mL×2) and driedin air to afford additional 150 mg of the title compound (1.0 g intotal, 80% yield). HPLC/MS (method A): retention time=3.24 min,(M+H)⁺=357.0. ¹H NMR (DMSO-d₆, 400 MHz): δ12.92 (s, 1H), 7.92 (s, 1H),7.62-7.70 (m, 1H), 7.35-7.50 (m, 3H), 7.33 (d, J=8.0 Hz, 2H), 7.20 (d,J=8.0 Hz, 2H).

1H. Preparation of3-chloro-6-(2-chlorophenyl)-7-(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazine

A suspension of6-(2-chlorophenyl)-7-(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one(1.0 g, 2.8 mmol) in phosphorus oxychloride (10 mL) was stirred at 130°C. for 6 h. Analysis by HPLC/MS indicated the starting material had beenconsumed. After cooling to room temperature, the reaction mixture wasconcentrated under reduced pressure. The obtained residue was dilutedwith CH₂Cl₂, the resulting solution washed with saturated aqueousNaHCO₃, saturated aqueous NaCl, dried (Na₂SO₄) and concentrated underreduced pressure to afford 1.1 g (100%) of the title compound as anoff-white solid. HPLC/MS (method A): retention time=3.52 min,(M+H)⁺=375.0.

1I. Preparation of6-(2-chlorophenyl)-7-(4-chlorophenyl)-N-cyclohexyl-[1,2,4]triazolo[4,3-b]pyridazin-3-amine

A suspension of3-chloro-6-(2-chlorophenyl)-7-(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazine(38 mg, 0.1 mmol) in cyclohexylamine (0.5 mL) was stirred at 100° C. for16 h. After cooling to room temperature, the reaction mixture wasconcentrated under reduced pressure. The residue was diluted with EtOAc(30 mL), washed with H₂O, saturated aqueous NaCl, dried (Na₂SO₄),filtered and concentrated under reduced pressure. The crude product waspurified using a silica gel cartridge (12 g) eluting with a gradient ofEtOAc (40-100%) in hexanes to afford 18 mg (41%) of the title compoundas a yellow powder. HPLC/MS (method A): retention time=3.58 min,(M+H)⁺=438.1. ¹H NMR (CDCl₃, 400 MHz): δ7.87 (s, 1H), 7.35-7.43 (m, 3H),7.30-7.33 (m, 1H), 7.20 (d, J=8.56 Hz, 2H), 7.04 (d, J=8.31Hz, 2H), 4.83(s, 1H), 3.98 (s, 1H), 2.22-2.25 (m, 2H), 1.79 (dd, J=9.78, 3.67 Hz,2H), 1.63-1.72 (m, 1H), 1.41-1.52 (m, 2H), 1.27-1.39 (m, 2H), 1.21-1.26(m, 1H).

Example 2 1I. Preparation of6-(2-chlorophenyl)-7-(4-chlorophenyl)-3-(piperidin-1-yl)-[1,2,4]triazolo[4,3-b]pyridazine

A suspension of3-chloro-6-(2-chlorophenyl)-7-(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazine(22 mg, 0.06 mmol) in piperidine (0.5 mL) was stirred at 100° C. for 16h. After cooling to room temperature, the reaction mixture wasconcentrated under reduced pressure. The crude product was purifiedusing reverse phase preparative HPLC (Conditions: Phenomenex Luna 5μ C1821.2×100 mm; Eluted with 60% to 100% B, 8 min gradient, 100% B hold for7 min, (A=90% H₂O, 10% MeOH, 0.1% trifluoroacetic acid and B=10% H₂O,90% MeOH, 0.1% trifluoroacetic acid); Flow rate at 20 mL/min, UVdetection at 220 nm). The desired fractions were concentrated underreduced pressure. The residue was dissolved in EtOAc, washed withsaturated aqueous NaHCO₃, water, saturated aqueous NaCl, dried (Na₂SO₄),filtered and concentrated under reduced pressure. The residue waslyophilized in acetonitrile to afford 12 mg (48%) of the title compoundas a yellow powder. HPLC/MS (method A): retention time=3.82 min,(M+H)⁺=424.1. ¹H NMR (CDCl₃, 400 MHz): δ7.92 (s, 1H), 7.29-7.39 (m, 4H),7.21 (d, J=8.56 Hz, 2H), 7.04 (d, J=8.56 Hz, 2H), 3.66 (s, 4H),1.72-1.81 (m, 4H), 1.69 (d, J=4.89 Hz, 2H).

Example 3 Preparation of1-(6-(2-chlorophenyl)-7-(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)-3-(ethylamino)pyrrolidine-3-carboxamide

A suspension of3-chloro-6-(2-chlorophenyl)-7-(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazine(113 mg, 0.3 mmol) and 3-(ethylamino)pyrrolidine-3-carboxamide (94 mg,0.6 mmol) in ethylene glycol (2 mL) was stirred at 110° C. for 2 h.Analysis by HPLC/MS indicated the reaction was not complete. Additional3-(ethylamino)pyrrolidine-3-carboxamide (47 mg, 0.3 mmol) was added. Thereaction continued at 110° C. for 1 h more. After cooling to roomtemperature, the reaction mixture was loaded onto a silica gel cartridge(12 g), eluted with a gradient of MeOH (0-6%) in CH₂Cl₂ to obtain 40 mgof desired product with 90% purity. The product was further purifiedusing reverse phase preparative HPLC (Conditions: Phenomenex Luna 5μ C1821.2×100 mm; Eluted with 40% to 90% B, 8 min gradient, 90% B hold for 3min, (A=90% H₂O, 10% MeOH, 0.1% trifluoroacetic acid and B=10% H₂O, 90%MeOH, 0.1% trifluoroacetic acid); Flow rate at 20 mL/min, UV detectionat 220 nm) to yield the product as a TFA salt. The product was dissolvedin EtOAc, washed with saturated aqueous NaHCO₃, water, saturated aqueousNaCl, dried (Na₂SO₄), filtered and concentrated under reduced pressure.The residue was lyophilized in acetonitrile to afford 30 mg (20%) of thetitle compound as a yellow powder. HPLC/MS (method A): retentiontime=2.75 min, (M+H)⁺=496.2. ¹H NMR (CDCl₃, 400 MHz): δ7.81 (s, 1H),7.28-7.38 (m, 4H), 7.19-7.26 (m, 2H), 7.01-7.07 (m, 2H), 5.39 (s, 1H),4.00-4.15 (m, 5H), 2.54-2.65 (m, 3H), 2.12 (m, 1H), 1.40-1.55 (m, 1H),1.10 (t, J=7.09 Hz, 3H).

Example 4 Preparation of1-(6-(2-chlorophenyl)-7-(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)-3-(ethylamino)azetidine-3-carboxamide

The title compound (70 mg, 32%) as a yellow powder was prepared from3-chloro-6-(2-chlorophenyl)-7-(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazine(168 mg, 0.45 mmol) and 3-(ethylamino)azetidine-3-carboxamide (291 mg,1.35 mmol) in a manner analogous to that in which1-(6-(2-chlorophenyl)-7-(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)-3-(ethylamino)pyrrolidine-3-carboxamidewas prepared. HPLC/MS (method A): retention time=2.76 min, (M+H)⁺=482.2.¹H NMR (DMSO-d6, 400 MHz): δ8.19 (s, 1H), 7.59-7.64 (m, 1H), 7.39-7.48(m, 3H), 7.28-7.37 (m, 3H), 7.17-7.25 (m, 3H), 4.44 (d,J=8.07 Hz, 2H),4.08 (d,J=8.07 Hz, 2H), 2.84 (bs, 1H), 2.41 (m, 2H), 1.02 (t, J=7.09 Hz,3H).

Example 5 Preparation of6-(2-chlorophenyl)-7-(4-chlorophenyl)-3-(cyclohexyloxy)-[1,2,4]triazolo[4,3-b]pyridazine

To a solution of cyclohexanol (0.5 g, 5 mmol) in anhydrous THF (1 mL) atroom temperature was added freshly cut sodium metal (35 mg, 1.5 mmol).The reaction mixture was stirred at room temperature for 20 min, then at60° C. for 30 min, and then allowed to cool to room temperature. Intothis mixture was added3-chloro-6-(2-chlorophenyl)-7-(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazine(115 mg, 0.3 mmol), the resulting mixture was stirred at roomtemperature under argon for 16 h. The reaction was carefully quenched byaddition of methanol, then diluted with EtOAc. The solution was washedwith H₂O, saturated aqueous NaCl, dried (Na₂SO₄), filtered andconcentrated. The obtained residue was purified using a silica gelcartridge (12 g) eluting with a gradient of EtOAc (0-40%) in hexanes toafford 10 mg (7.6%) of the title compound as a pale-yellow solid.HPLC/MS (method A): retention time=4.06 min, (M+H)⁺=439.1. ¹H NMR(CDCl₃, 400 MHz): δ7.84 (s, 1H), 7.46 (dd, J=5.62, 3.67 Hz, 1H),7.32-7.37 (m, 2H), 7.25-7.30 (m, 1H), 7.20 (d, J=8.56 Hz, 2H), 7.03-7.08(m, 2H), 5.21-5.29 (m, 1H), 2.28 (d, J=12.96 Hz, 2H), 1.88 (d, J=4.40Hz, 2H), 1.60-1.80 (m, 3H), 1.45-1.52 (m, 2H), 1.20-1.40(m, 1H).

Example 6 Preparation of6-(2-chlorophenyl)-7-(4-chlorophenyl)-3-(2,2,2-trifluoroethoxy)-[1,2,4]triazolo[4,3-b]pyridazine

A mixture3-chloro-6-(2-chlorophenyl)-7-(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazine(38 mg, 0.1 mmol), 2,2,2-trifluoroethanol (22 μL, 0.2 mmol),2-tert-butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diazaphosphorine(60 μL, 0.3 mmol) and anhydrous THF (0.5 mL) in a sealed tube wasstirred at 70° C. for 3 days. After cooling to room temperature, thereaction mixture was concentrated under reduced pressure. The obtainedresidue was purified using reverse phase preparative HPLC (Conditions:Phenomenex Luna 5μ C18 21.2×100 mm; Eluted with 60% to 100% B, 10 mingradient, 100% B hold for 5 min, (A=90% H₂O, 10% MeOH and B=10% H₂O, 90%MeOH); Flow rate at 20 mL/min, UV detection at 220 nm) to yield 30 mg ofthe desired product with 90% purity. The impure product was furtherpurified using a silica gel cartridge (4 g) eluting with a gradient ofEtOAc (30-100%) in hexanes to afford 24 mg (55%) of the title compoundas a white solid. HPLC/MS (method A): retention time=3.81 min,(M+H)⁺=439.1. ¹H NMR (CDCl₃, 400 MHz): δ7.92 (s, 1H), 7.40-7.49 (m, 1H),7.29-7.33 (m, 2H), 7.14-7.30 (m, 3H), 7.09 (d, J=8.56 Hz, 2H), 5.05-5.07(m, 2H).

Example 7 Preparation of6-(2-chlorophenyl)-7-(4-chlorophenyl)-3-(cyclohexylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine

7A. Preparation ofN′-(6(2-chlorophenyl)-5-(4-chlorophenyl)pyridazin-3-yl)-2-cyclohexylacetohydrazide

To a solution of cyclohexylacetic acid (85 mg, 0.6 mmol) in THF (3 mL)at 0° C. was added 4-methylmorpholine (86 μL, 0.78 mmol), followed byiso-butyl chloroformate (78 μL, 0.6 mmol) dropwise. The reaction mixturewas stirred at 0° C. for 30 min, then a suspension of1-(6-(2-chlorophenyl)-5-(4-chlorophenyl)pyridazin-3)hydrazine (99 mg,0.3 mmol) in THF (2 mL) was added to the above mixture. After addition,the reaction mixture was stirred at 0° C. for 1 h, then filtered. Thecollected solid was washed with EtOAc (20 mL×2). The combined organicwas washed with H₂O, saturated aqueous NaCl, and concentrated underreduced pressure. The obtained residue was triturated with EtOAc (2mL×2) to afford 47 mg (34%) of the title compound as an off-white solid.HPLC/MS (method A): retention time=3.53 min, (M+H)⁺=455.2.

7B. Preparation of6-(2-chlorophenyl)-7-(4-chlorophenyl)-3-(cyclohexylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine

To a suspension ofN′-(6-(2-chlorophenyl)-5-(4-chlorophenyl)pyridazin-3-yl)-2-cyclohexylacetohydrazide(46 mg, 0.1 mmol) in THF (2 mL) at room temperature was addeddiisopropylethylamine (0.14 mL, 0.8 mmol). After 5 min,triphenylphosphine dichloride (110 mg, 0.33 mmol) was added, and thereaction mixture stirred at room temperature for 16 h. Analysis byHPLC/MS indicated the reaction was complete. The reaction was dilutedwith EtOAc (40 mL), washed with H₂O, saturated aqueous NaCl, dried(Na₂SO₄), filtered and concentrated. The obtained residue was purifiedusing a silica gel cartridge (12 g) eluting with a gradient of EtOAc(0-30%) in hexanes to yield 45 mg of the desired product with 80% purity(contaminated with triphenylphosphine oxide). The product was furtherpurified using reverse phase preparative HPLC (Conditions: PhenomenexLuna 5 μC18 21.2×100 mm; Eluted with 70% to 100% B, 8 min gradient, 100%B hold for 7 min, (A=90% H₂O, 10% MeOH and B=10% H₂O, 90% MeOH); Flowrate at 20 mL/min, UV detection at 220 nm) to afford 30 mg (68%) of thetitle compound as a white powder. HPLC/MS (method A): retentiontime=4.22 min, (M+H)⁺=437.1. ¹H NMR (CDCl₃, 400 MHz): δ8.03 (s, 1H),7.33-7.41 (m, 4H), 7.21-7.28 (m, 2H), 7.07 (d, J=8.31Hz, 2H), 3.14 (d,J=7.09 Hz, 2H), 2.01-2.12 (m, 1H), 1.69-1.80 (m, 4H), 1.21-1.29 (m, 3H),1.10-1.17 (m, 3H).

EXAMPLE 8 Preparation of3-benzyl-6-(2-chlorophenyl)-7-(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazine

8A. Preparation ofN′-(6-(2-chlorophenyl)-5-(4-chlorophenyl)pyridazin-3-yl)-2-phenylacetohydrazide

The title compound (42 mg, 47%) as a white foam was prepared from2-phenylacetic acid (41 mg, 0.3 mmol) and1-(6-(2-chlorophenyl)-5-(4-chlorophenyl)pyridazin-3)hydrazine (66 mg,0.2 mmol) according to the procedures described forN′-(6-(2-chlorophenyl)-5-(4-chlorophenyl)pyridazin-3-yl)-2-cyclohexylacetohydrazide(Example 7A). HPLC/MS (method A): retention time =3.30 min,(M+H)⁺=449.2.

8B. Preparation of3-benzyl-6-(2-chlorophenyl)-7-(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazine

The title compound (20 mg, 54%) as a white powder was prepared fromN′-(6-(2-chlorophenyl)-5-(4-chlorophenyl)pyridazin-3-yl)-2-phenylacetohydrazide(38 mg, 0.085 mmol) and triphenylphosphine dichloride (85 mg, 0.26 mmol)according to the procedures described for6-(2-chlorophenyl)-7-(4-chlorophenyl)-3-(cyclohexylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine(Example 7B). HPLC/MS (method A): retention time=3.92 min, (M+H)⁺=431.2.

Example 9 Preparation of6-(2-chlorophenyl)-7-(4-chlorophenyl)-3-(tetrahydro-2H-pyran-4-yl)methyl)-[1,2,4]triazolo[4,3-b]pyridazine

9A. Preparation ofN′-(6-(2-chlorophenyl)-5-(4-chlorophenyl)pyridazin-3-yl)-2-(tetrahydro-2H-pyran4-yl)acetohydrazide

To a solution of 2-(tetrahydro-2H-pyran-4-yl)acetic acid (86.5 mg, 0.6mmol) in anhydrous DMF (1 mL) was added HOBt (162 mg, 1.2 mmol),followed by EDAC (230 mg, 1.2 mmol). After addition, the reactionmixture was stirred at room temperature for 1.5 h, then a solution of1-(6-(2-chlorophenyl)-5-(4-chlorophenyl)pyridazin-3)hydrazine (99 mg,0.3 mmol) in DMF (2 mL) was added. The mixture was stirred at roomtemperature for 16 h, then diluted with water, extracted with EtOAc (20mL×3). The combined organic was washed with saturated aqueous NaCl,dried (Na₂SO₄) and concentrated under reduced pressure. The crudeproduct was purified using a silica gel cartridge (12 g) eluting with agradient of EtOAc (20-100%) in hexanes to afford 21 mg (15%) of thetitle compound as a white foam. HPLC/MS (method A): retention time=2.95min, (M+H)⁺=457.2.

9B. Preparation of6-(2-chlorophenyl)-7-(4-chlorophenyl)-3-(tetrahydro-2H-pyran-4-yl)methyl)-[1,2,4]triazolo[4,3-b]pyridazine

The title compound (8 mg, 40%) as a white powder was prepared fromN′-(6-(2-chlorophenyl)-5-(4-chlorophenyl)pyridazin-3-yl)-2-(tetrahydro-2H-pyran-4-yl)acetohydrazide(21 mg, 0.046 mmol) according to the procedures described for6-(2-chlorophenyl)-7-(4-chlorophenyl)-3-(cyclohexylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine(Example 7B). HPLC/MS (method A): retention time=3.57 min, (M+H)⁺=439.2.¹H NMR (CDCl₃, 400 MHz): δ8.05 (s, 1H), 7.30-7.42 (m, 4H), 7.23 (d,J=8.31 Hz, 2H), 7.06-7.10 (m, 2H), 3.97 (dd, J=11.62, 2.81 Hz, 2H), 3.41(td, J=11.74, 1.96 Hz, 2H), 3.21 (d, J=7.09 Hz, 2H), 2.25-2.42 (m, 1H),1.71 (dd, J=12.84, 1.59 Hz, 2H), 1.43-1.55 (m, 2H).

Example 10 Preparation of3-(4-chlorobenzyl)-6-(2-chlorophenyl)-7-(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazine

10A. Preparation of2-(4-chlorophenyl)-N′-(6-(2-chlorophenyl)-5-(4-chlorophenyl)pyridazin-3-yl)acetohydrazide

The title compound (90 mg, 62%) as a white solid was prepared from2-(4-chlorophenyl)acetic acid (62 mg, 0.36 mmol) and1-(6-(2-chlorophenyl)-5-(4-chlorophenyl)pyridazin-3)hydrazine (99 mg,0.3 mmol) according to the procedures described forN′-(6-(2-chlorophenyl)-5-(4-chlorophenyl)pyridazin-3-yl)-2-(tetrahydro-2H-pyran-4-yl)acetohydrazide(Example 9A). HPLC/MS (method A): retention time=3.57 min, (M+H)⁺=483.2.

10B. Preparation of3-(4-chlorobenzyl)-6-(2-chlorophenyl)-7-(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazine

The title compound (50 mg, 54%) as a white powder was prepared from2-(4-chlorophenyl)-N′-(6-(2-chlorophenyl)-5-(4-chlorophenyl)pyridazin-3-yl)acetohydrazide(96 mg, 0.2 mmol) and triphenylphosphine dichloride (220 mg,0.66 mmol)according to the procedures described for6-(2-chlorophenyl)-7-(4-chlorophenyl)-3-(cyclohexylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine(Example 7B). HPLC/MS (method A): retention time=4.12 min, (M+H)⁺=465.2.

Example 11 Preparation of6-(2-chlorophenyl)-7-(4-chlorophenyl)-3-(4-(trifluoromethyl)benzyl)-[1,2,4]triazolo[4,3-b]pyridazine

11A. Preparation ofN′-(6-(2-chlorophenyl)-5-(4-chlorophenyl)pyridazin-3-yl)-2-(4-(trifluoromethyl)phenyl)acetohydrazide

To a solution of 2-(4-(trifluoromethyl)phenyl)acetic acid (98 mg, 0.48mmol), HOBt (150 mg, 0.78 mmol), diisopropylethylamine (0.18 mL, 1.0mmol) in anhydrous DMF (2 mL) was added EDAC (105 mg, 0.78 mmol),followed by1-(6-(2-chlorophenyl)-5-(4-chlorophenyl)pyridazin-3)hydrazine (132 mg,0.4 mmol). After addition, the reaction mixture was stirred at roomtemperature for 16 h, then quenched by addition of water. The aqueousmixture was extracted with EtOAc (30 mL×2). The combined organic waswashed with saturated aqueous NaCl, dried (Na₂SO₄) and concentratedunder reduced pressure. The crude product was purified using a silicagel cartridge (12 g) eluting with a gradient of EtOAc (20-100%) inhexanes to afford 130 mg (63%) of the title compound as a white solid.HPLC/MS (method A): retention time=3.70 min, (M+H)⁺=571.1.

11B. Preparation of6-(2-chlorophenyl)-7-(4-chlorophenyl)-3-(4-(trifluoromethyl)benzyl)-[1,2,4]triazolo[4,3-b]pyridazine

A solution ofN′-(6-(2-chlorophenyl)-5-(4-chlorophenyl)pyridazin-3-yl)-2-(4-(trifluoromethyl)phenyl)acetohydrazide(124 mg, 0.24 mmol) and acetic acid (69 μL, 1.2 mmol) in ethanol (2.5mL) in a vial was heated in a microwave oven at 180° C. for 30 min.After cooling to room temperature, the reaction mixture was diluted withEtOAc, washed with saturated aqueous NaHCO₃, saturated aqueous NaCl,dried (Na₂SO₄), filtered and concentrated under reduced pressure. Thecrude product was purified using a silica gel cartridge (12 g) elutingwith a gradient of EtOAc (0-70%) in hexanes to obtain 100 mg of thedesired product with 96% purity. The product was crystallized frommethanol (2 mL) to yield 42 mg of the pure product as a white solid. Themother liquid was concentrated. The obtained residue was purified usingreverse phase preparative HPLC (Conditions: Phenomenex Luna 5μ C1821.2×100 mm; Eluted with 70% to 100% B, 10 min gradient, 100% B hold for4 min, (A=90% H₂O, 10% MeOH and B=10% H₂O, 90% MeOH); Flow rate at 20mL/min, UV detection at 220 nm) to afford additional 48 mg of the titlecompound as a white powder (90 mg in total, 75% yield). HPLC/MS (methodA): retention time =4.08 min, (M+H)⁺=499.3.

Examples 12 TO 26

The examples shown below in Table 1 were prepared from1-(6-(2-henyl)-5-(4-chlorophenyl)pyridazin-3)hydrazine and thecorresponding carboxylic acids (R—CO₂H in Table 1) in a manner analogousto that in which6-(2-henyl)-7-(4-chlorophenyl)-3-(4-(trifluoromethyl)benzyl)-[1,2,4]triazolo[4,3-b]pyridazine (Example 11) was prepared. TABLE 1HPLC/MS (method A) HPLC/MS Example R R—CO₂H retention time [M + H]⁺ 12

3,3,3-trifluoro-propanoic acid 3.63 423.1 13

4,4,4-trifluoro-butanoic acid 3.76 437.2 14

4,4,4-trifluoro-3- methylbutanoic acid 3.99 451.1 15

2-(dimethylamino)-acetic acid 2.79 398.2 16

cyclohexane-carboxylic acid 4.18 423.2 17

4-methoxybicyclo [2.2.1]heptane-1-carboxylic acid 3.88 465.2 18

4-methoxybicyclo [2.2.1]octane-1-carboxylic acid 3.91 479.3 19

2-(1-(tert-butoxy carbonyl)piperidin-4- yl)acetic acid 3.93 538.1 20

2-(6-chloropyridin-3- yl)acetic acid 3.70 466.2 21

2-hydroxy-2-(4-(trifluoromethyl) phenyl)acetic acid 3.91 515.2 22

(S)-2-(tert- butoxycarbonylamino)-2- phenylacetic acid 3.67 504.3 23

2-(tert- butoxycarbonylamino)-2-(4- (trifluoromethyl) phenyl)acetic acid4.11 614.4 24

2-(6- (trifluoromethyl)pyridin-3- yl)acetic acid 3.61 500.1 25

2-(2-methyl-6- (trifluoromethyl)pyridin-3- yl)acetic acid 3.70 514.2 26

2-(2-methoxy-6- (trifluoromethyl)pyridin-3- yl)acetic acid 4.11 530.1

Example 27 Preparation of(1S)-(6-(2-chlorophenyl)-7-(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)(phenyl)methanamine

A solution of tert-butyl(1S)-(6-(2-chlorophenyl)-7-(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)(phenyl)methylcarbamate(Example 22) (37 mg, 0.068 mmol) in TFA (0.5 mL) and CH₂Cl₂ (0.5 mL) wasstirred at room temperature for 2 h. Analysis by HPLC/MS indicated thereaction was complete. The reaction mixture was concentrated underreduced pressure, and the obtained residue was dissolved in EtOAc. Theresulting solution was washed with saturated aqueous NaHCO₃, saturatedaqueous NaCl, dried (Na₂SO₄), filtered and concentrated under reducedpressure to afford 30 mg (100%) of the title compound as an off-whitesolid. HPLC/MS (method A): retention time=3.11 min, (M+H)⁺=429.2.

Example 28 Preparation of methyl(1S)-(6-(2-chlorophenyl)-7-(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)(phenyl)methylcarbamate

To a solution of(1S)-(6-(2-chlorophenyl)-7-(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)(phenyl)methanamine(30 mg, 0.067 mmol) in anhydrous THF (1 mL) at room temperature wasadded saturated aqueous NaHCO₃ solution (1 mL), followed by methylchloroformate (2 drops). After addition, the reaction mixture wasstirred at room temperature for 15 min. Analysis by HPLC/MS indicatedthe reaction was complete. The reaction mixture was extracted with EtOAc(15 mL×2). The combined organic was washed with saturated aqueous NaCl,dried (Na₂SO₄), filtered and concentrated under reduced pressure. Thecrude product was purified using a silica gel cartridge (12 g) elutingwith a gradient of EtOAc (20-100%) in hexanes to afford 25 mg (74%) ofthe title compound as a white foam. HPLC/MS (method A): retentiontime=3.67 min, (M+H)⁺=504.3.

Example 29 Preparation of6-(2-chlorophenyl)-7-(4-chlorophenyl)-3-(piperidin-4-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine,hydrochloride Salt

To a solution of tert-butyl4-((6-(2-chlorophenyl)-7-(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)piperidine-1-carboxylate(Example 19) (0.6 g, 1.11 mmol) in CH₂Cl₂ (15 mL) was added 2 M HCl indiethyl ether (5 mL. The resulting mixture was stirred at roomtemperature for 2 h, then concentrated under reduced pressure. Theobtained residue was evaporated with CH₂Cl₂ three times, dried in highvacuum overnight to afford 450 mg (85%) of the title compound as anoff-white powder. HPLC/MS (method A): retention time=3.01 min,(M+H)⁺=438.2.

Example 30 Preparation of4-(6(2-chlorophenyl)-7-(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)bicyclo[2.2.2]octan-1-ol

To a suspension of6-(2-chlorophenyl)-7-(4-chlorophenyl)-3-(4-methoxybicyclo[2.2.2]octan-1-yl)-[1,2,4]triazolo[4,3-b]pyridazine(Example 18) (48 mg, 0.1 mmol) in aqueous (48%) hydrobromic acidsolution (0.37 mL) was added dropwise acetic anhydride (0.33 mL). Afteraddition, the reaction tube was sealed, and heated at 120° C. for 16 h.After cooling to room temperature, the reaction mixture was adjusted topH 7-8 by careful addition of saturated aqueous NaHCO₃, then extractedwith EtOAc (10 mL×2). The combined organic was washed with water,saturated aqueous NaCl, dried (Na₂SO₄), filtered and concentrated underreduced pressure. The crude product was purified using reverse phasepreparative HPLC (Conditions:Phenomenex Luna 5μC18 21.2×100 mm; Elutedwith 70% to 100% B, 18 min gradient, 100% B hold for 3 min, (A=90% H₂O,10% MeOH and B=10% H₂O, 90% MeOH); Flow rate at 20 m/min, UV detectionat 220 nm) to afford 35 mg (75%) of the title compound as a white solid.HPLC/MS (method A): retention time=3.61 min, (M+H)⁺=465.2.

Example 31 Preparation of4-(6-(2-chlorophenyl)-7-(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)bicyclo[2.2.1] heptan-1-ol

The title compound (36 mg, 79%) as a light yellow foam was prepared from6-(2-chlorophenyl)-7-(4-chlorophenyl)-3-(4-methoxybicyclo[2.2.1]heptan-1-yl)-[1,2,4]triazolo[4,3-b]pyridazine(Example 17) (47 mg, 0.1 mmol) according to the procedures described for4-(6-(2-chlorophenyl)-7-(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)bicyclo[2.2.2]octan-1-ol(Example 30). HPLC/MS (method A): retention time=3.60 min, (M+H)⁺=451.2.

Example 32 Preparation of3-((6-(2-chlorophenyl)-7-(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)-6-(trifluoromethyl)pyridin-2-ol

A suspension of6-(2-chlorophenyl)-7-(4-chlorophenyl)-3-((2-methoxy-6-(trifluoromethyl)pyridin-3-yl)methyl)-[1,2,4]triazolo[4,3-b]pyridazine(Example 26) (100 mg, 0.19 mmol) in aqueous (48%) hydrobromic acid (2mL) was refluxed for 1 h. After cooling to room temperature, thereaction mixture was adjusted to pH 7-8 by careful addition of saturatedaqueous NaHCO₃. The resulting suspension was filtered, and the collectedsolid was washed with water (10 mL×2), diethyl ether (5 mL), dried in a50° C. vacuum oven overnight to afford 60 mg (62%) of the title compoundas an off-white solid. HPLC/MS (method A): retention time=3.53 min,(M+H)⁺=516.0.

Example 33 Preparation of ethyl6-(2-chlorophenyl)-7-(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazine-3-carboxylate

To a solution of5-(2-chlorophenyl)-4-(4-chlorophenyl)-2-hydrazinylpyridine (258 mg, 0.78mmol) in THF at room temperature was added acetic acid (0.18 mL, 3.12mmol), followed by ethyl glyoxylate (0.16 mL, 0.78 mmol). Afteraddition, the reaction mixture was stirred at room temperature for 16 h.Analysis by HPLC/MS indicated the reaction was complete. The reactionwas concentrated under reduced pressure. The obtained residue wasdissolved in acetic acid (4 mL). To this solution was added sodiumacetate (256 mg, 3.12 mmol), followed by dropwise addition of a solutionof bromine (36 μL, 0.7 mmol) in acetic acid (0.5 mL). After addition,the reaction mixture was stirred at room temperature for 16 h, thenheated in a microwave oven at 150° C. for 15 min. After cooling to roomtemperature, the reaction mixture was concentrated under reducedpressure. The residue was taken into EtOAc (30 mL), washed withsaturated aqueous NaHCO₃, saturated aqueous NaCl, dried (Na₂SO₄) andconcentrated. The crude product was purified using a silica gelcartridge (40 g) eluting with a gradient of EtOAc (20-100%) in hexanesto afford 210 mg (65%) of the title compound as an off-white solid.HPLC/MS (method A): retention time=3.53 min, (M+H)⁺=413.2.

Example 34 Preparation of6(2-chlorophenyl)-7-(4-chlorophenyl)-N-(4-(trifluoromethyl)benzyl)-[1,2,4]triazolo[4,3-b]pyridazine-3-carboxamide

A solution of ethyl6-(2-chlorophenyl)-7-(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazine-3-carboxylate(41 mg, 0.10 mmol) and (4-(trifluoromethyl)phenyl) methanamine (29 μL,0.2 mmol) in methanol (0.5 mL) was stirred at room temperature for 16 h.Analysis by HPLC/MS indicated the staring material had been consumed.The resulting suspension was filtered, the collected solid was washedwith hexanes (5 mL×2), dried in air to afford 22 mg (41%) of the titlecompound as a white solid. HPLC/MS (method A): retention time =3.93 min,(M+H)⁺=542.2.

Examples 35 TO 41

The examples shown below in Table 2 were prepared from ethyl6-(2-chlorophenyl)-7-(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazine-3-carboxylate (Example 33) and thecorresponding amines in a manner analogous to that in which6-(2-chlorophenyl)-7-(4-chlorophenyl)-N-(4-(trifluoromethyl)benzyl)-[1,2,4]triazolo[4,3-b]pyridazine-3-carboxamide(Example 34) was prepared. TABLE 2 HPLC/MS (method A) HPLC/MS Example RAmine retention time [M + H]⁺ 35

piperidine 3.49 452.2 36

morpholine 3.17 454.2 37

piperidin-4-ol 3.06 468.2 38

cyclohexylamine 3.84 466.2 39

cyclohexyl-methanamine 4.00 480.3 40

benzylamine 3.90 474.3 41

2-phenylethanamine 4.05 488.3

Example 42 Preparation of(4-benzylpiperidin-1-yl)(6-(2-chlorophenyl)-7-(4-chlorophenyl)-[1,2,4]triazolo [4,3-b]pyridazin-3-yl)methanone

A solution of ethyl6-(2-chlorophenyl)-7-(4-chlorophenyl)-triazolo[4,3-b]pyridazine-3-carboxylate(21 mg, 0.05 mmol) and 4-benzylpiperidine (0.175 mL, 1.0 mrnmol) inmethanol (0.5 mL) was heated in a microwave oven at 160° C. for 30 min.After cooling to room temperature, the reaction mixture was concentratedunder reduced pressure, then the crude product was purified usingreverse phase preparative HPLC (Conditions: Water SunFire Prep C18, OBD19×100 m, 5 □m; Eluted with 0% to 100% B, 10 min gradient, 100% B holdfor 5 min, (A=90% H₂O, 10% MeOH, 0.1% of TFA and B=10% H₂O, 90% MeOH,0.1% of TFA); Flow rate at 20 mL/min, UV detection at 220 nm) to afford18 mg (66%) of the title compound as a white powder. HPLC/MS (method A):retention time=4.12 min, (M+H)⁺=542.1.

Examples 43 TO 52

The examples shown below in Table 3 were prepared from ethyl6-(2-chlorophenyl)-7-(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazine-3-carboxylate(Example 33) and the corresponding amines in a manner analogous to thatin which(4-benzylpiperidin-1-yl)(6-(2-chlorophenyl)-7-(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methanone (Example 42) was prepared.TABLE 3 HPLC/MS (method A) HPLC/MS Example R Amine retention time [M +H]⁺ 43

pentan-3-amine 3.78 454.2 44

2,6-dimethyl morpholine 3.55 482.1 45

piperidin-4-ylmethanol 3.26 482.2 46

4-phenyl-piperidin-4-ol 3.64 544.1 47

4-phenylpiperidine 3.87 528.2 48

(3-(trifluoromethyl) phenyl)methanamine 3.92 542.1 49

benzylamine 3.73 474.1 50

N-methyl-benzylamine 3.70 488.1 51

2-phenylethanamine 3.80 488.1 52

N-methyl-2- phenylethanamine 3.75 502.1

Example 53 Preparation of6-(2-chlorophenyl)-7-(4-chlorophenyl)-N-methyl-N-(4-rifluoromethyl)benzyl)-[1,2,4]triazolo[4,3-b]pyridazine-3-carboxamide

To a solution of6-(2-chlorophenyl)-7-(4-chlorophenyl)-N-(4-(trifluoromethyl)benzyl)-[1,2,4]triazolo[4,3-b]pyridazine-3-carboxamide Example 34) (22mg, 0.041 mmol) in anhydrous DMF at room temperature was added sodiumhydride (6.5 mg, 0.164 mmol). The resulting suspension was stirred atroom temperature for 5 min, then iodomethane (25 μL, 0.4 mmol) wasadded. The reaction mixture was stirred at room temperature for 1 h. Themixture was diluted with EtOAc (30 mL), washed with water, saturatedaqueous NaCl, dried (Na₂SO₄) and concentrated under reduced pressure.The crude product was purified using a silica gel cartridge (4 g)eluting with a gradient of EtOAc (0-60%) in hexanes to afford 15 mg(66%) of the title compound as a white powder. HPLC/MS (method A):retention time=3.85 min, (M+H)⁺=556.3

Example 54 Preparation of6-(2-chlorophenyl)-7-(4-chlorophenyl)-3-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-[1,2,4]triazolo[4,3-a]pyridine

54A. Preparation of 5-chloro-4-(4-chlorophenyl)-2-fluoropyridine

A suspension of 5-chloro-2-fluoro-4-iodopyridine (2.57 g, 10 mmol),4-chlorophenylboronic acid (1.72 g, 11 mmol) and Pd(Ph₃P)₄ (462 mg, 0.4mmol) in a mixture of 2.0 M aqueous sodium carbonate (6 mL) and toluene(10 mL) was heated at 140 ° C. in a microwave oven for 30 min. Analysisby HPLC/MS indicated that the reaction was not complete. Additonal4-chlorophenylboronic acid (0.156 g, 1 mmol) was added, followed byPd(Ph₃P)₄ (116 mg, 0.1 mmol). The reaction mixture was again heated at140° C. in a microwave oven for 30 min. After cooling to roomtemperature, the reaction mixture was diluted with water and extractedwith EtOAc (50 mL×3). The combined EtOAc extracts were washed withsaturated aqueous NaCl, dried over Na₂SO₄, filtered and concentratedunder reduced pressure. The crude product was purified using a silicagel cartridge (120 g) eluted with a gradient of EtOAc (0-50%) in hexanesto afford 2.6 g of the product (˜60% pure) as an off-white solid. Thiswas crystallized in EtOAc-hexanes to obtain the pure title compound (0.9g) as a white solid. HPLC/MS: retention time=3.80 min, [M+H]⁺=242.0.

54B. Preparation of5-(2-chlorophenyl)4-(4-chlorophenyl)-2-fluoropyridine

To a flame-dried tube was placed5-chloro-4-(4-chlorophenyl)-2-fluoropyridine (0.71 g, 2.93 mmol),2-chlorophenylboronic acid (0.55 g, 3.52 mmol), K₃PO₄ (1.24 g, 5.86mmol), Pd₂(dba)₃ (0.134 g, 0.147 mmol), and S-Phos (0.12 g, 0.29 mmol).The reaction vessel was then purged with argon three times beforedegassed toluene (15 mL) was added in, and sealed. The reaction mixturewas stirred at 95° C. for 16 h. Analysis by HPLC/MS indicated thereaction was complete. After cooling to room temperature, the reactionmixture was partitioned between EtOAc and water. The aqueous layer wasextracted with EtOAc (30 mL×3). The combined organic was washed withsaturated aqueous NaCl, dried over Na₂SO₄, filtered and concentratedunder reduced pressure. The crude product was purified using a silicagel cartridge (80 g) eluting with a gradient of EtOAc (0-10%) in hexanesto afford 0.33 g (35%) of the title compound as a white foam. HPLC/MS:retention time=4.03 min, [M+H]⁺=318.1.

54C. Preparation of5-(2-chlorophenyl)-4-4-chlorophenyl)-2-hydrazinylpyridine.

To a suspension of5-(2-chlorophenyl)-4-(4-chlorophenyl)-2-fluoropyridine (0.32 g, 1 mmol)in pyridine (4 mL) at room temperature was added anhydrous hydrazine (1mL). The resulting mixture was stirred at 90° C. for 1 h. Analysis byHPLC/MS indicated the reaction was complete. After cooling to roomtemperature, the reaction mixture was concentrated under reducedpressure. To the residue was added water, and the resulting suspensionwas extracted with EtOAc (50 mL×3). The combined EtOAc extracts werewashed with saturated aqueous NaCl, dried over Na₂SO₄, filtered andconcentrated under reduced pressure to afford 0.28 g (85%) of the titlecompound as a white foam. HPLC/MS: retention time=3.03 min,[M+H]⁺=330.1.

54D. Preparation ofN′-(5-(2-chlorophenyl)4-(4-chlorophenyl)pyridin-2-yl)-2-(2-methyl-6-(trifluoromethyl)pyridin-3-yl)acetohydrazide

The title compound (80 mg, 99%) as a white solid was prepared from5-(2-chlorophenyl)-4-(4-chlorophenyl)-2-hydrazinylpyridine (50 mg, 0.15mmol) and 2-(2-methyl-6-(trifluoromethyl)pyridin-3-yl)acetic acid (49.3mg, 0.225 mmol) in a manner analogous to that in whichN′-(6-(2-chlorophenyl)-5-(4-chlorophenyl)pyridazin-3-yl)-2-(4-(trifluoromethyl)phenyl)acetohydrazide(Example 11 A) was prepared. HPLC/MS: retention time=3.63 min,[M+H]⁺=531.1.

54E. Preparation of6-(2-chlorophenyl)-7-(4-chlorophenyl)-3-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-[1,2,4]triazolo[4,3-a]pyridine

A solution ofN′-(5-(2-chlorophenyl)-4-(4-chlorophenyl)pyridin-2-yl)-2-(2-methyl-6-(trifluoromethyl)pyridin-3-yl)acetohydrazide(80 mg, 0.15 mmol) and acetic acid (0.5 mL) in ethanol (1 mL) was heatedin a microwave oven at 180° C. for 30 min. Analysis by HPLC/MS indicatedabout 40% of starting material remained. The reaction mixture was heatedagain in a microwave oven at 180° C. for additional 30 min. Aftercooling to room temperature, the reaction mixture was concentrated underreduced pressure. The obtained residue was taken into EtOAc, and thesolution was washed with saturated aqueous NaHCO₃, saturated aqueousNaCl dried (Na₂SO₄), filtered and concentrated under reduced pressure.The crude product was purified using reverse phase preparative HPLC(Conditions: Phenomenex Luna 5μ C18 21.2×100 mm; Eluted with 70% to 100%B, 10 min gradient, 100% B hold for 4 min, (A=90% H₂O, 10% MeOH andB=10% H₂O, 90% MeOH); Flow rate at 20 mL/min, UV detection at 220 nm) toyield the desired product with about 64% purity. The product was furtherpurified using a silica gel cartridge (12 g) eluting with a gradient ofEtOAc (0-70%) in hexanes to afford 18 mg (23%) of the title compound.HPLC/MS (method A): retention time=3.91 min, (M+H)⁺=513.1.

EXAMPLE 55 Preparation of6-(2-chlorophenyl)-7-(4-chlorophenyl)-3-((6-(trifluoromethyl)pyridin-3-yl)methyl)-[1,2,4]triazolo[4,3-a]pyridine

55A. Preparation ofN′-(5-(2-chlorophenyl)4-(4-chlorophenyl)pyridin-2-yl)-2-(6-(trifluoromethyl)pyridin-3-yl)acetohydrazide

The title compound (40 mg, 100%) as a white solid was prepared from5-(2-chlorophenyl)-4-(4-chlorophenyl)-2-hydrazinylpyridine (25 mg, 0.075mmol) and 2-(6-(trifluoromethyl)pyridin-3-yl)acetic acid (23 mg, 0.113mmol) in a manner analogous to that in whichN′-(6-(2-chlorophenyl)-5-(4-chlorophenyl)pyridazin-3-yl)-2-(4-(trifluoromethyl)phenyl)acetohydrazide(Example 11A) was prepared. HPLC/MS: retention time=3.53 min,[M+H]⁺=517.1.

55B. Preparation of6-(2-chlorophenyl)-7-(4-chlorophenyl)-3-((6-(trifluoromethyl)pyridin-3-yl)methyl)-[1,2,4]triazolo[4,3-a]pyridine

A solution ofN′-(5-(2-chlorophenyl)-4-(4-chlorophenyl)pyridin-2-yl)-2-(6-(trifluoromethyl)pyridin-3-yl)acetohydrazide(40 mg, 0.075 mmol) and acetic acid (0.25 mL) in ethanol (0.5 mL) washeated in a microwave oven at 180° C. for 45 min. After cooling to roomtemperature, the reaction mixture was concentrated under reducedpressure. The obtained residue was taken into EtOAc, and the solutionwas washed with saturated aqueous NaHCO₃, saturated aqueous NaCl, dried(Na₂SO₄), filtered and concentrated under reduced pressure. The crudeproduct was purified using a silica gel cartridge (12 g) eluting with agradient of EtOAc (0-70%) in hexanes to obtain the product with about85% purity as an oil. The product was further purified using reversephase preparative HPLC (Conditions: Phenomenex Luna 5μ C18 21.2×100 mm;Eluted with 50% to 100% B, 10 min gradient, 100% B hold for 4 min,(A=90% H₂O, 10% MeOH, 0.1% TFA and B=10% H₂O, 90% MeOH, 0.1% TFA); Flowrate at 20 mL/min, UV detection at 220 nm) to yield the desired product,which was taken into EtOAc, washed with saturated aqueous NaHCO₃,saturated aqueous NaCl, dried over Na₂SO₄, filtered and concentrated.The residue was lyophilized in acetonitrile to afford 9 mg (24% yield,99% pure) of the title compound as a white powder. HPLC/MS (method A):retention time=3.88 min, [M+H]⁺=499.0.

Example 56 Preparation of7-(4-chlorophenyl)-6-(2,4-dichlorophenyl)-3-((6(trifluoromethyl)pyridin-3-yl)methyl)-[1,2,4]triazolo[4,3-a]pyridine

56A. Preparation of 5-bromo-2-chloro-4-(4-chlorophenyl)pyridine

To a degassed solution of 5-bromo-2-chloro-4-iodopyridine (Ref. Cottet,F. and Schlosser, M. Tetrahedron 60, 11896-11874 (2004)) (2.0 g, 6.3mmol), 4-chlorophenylboronic acid (1.1 g, 6.9 mmol) and K₂CO₃ (1.7 g,12.6 mmol) in 1,2-dimethoxyethane (24 mL) and H₂0 (8.0 mL) was addedPd(PPh₃)₄ (0.727 g, 0.63 mmol) under argon at 20° C. The reactionmixture was refluxed for 15 h under argon, then allowed to cool to 20°C. The reaction was quenched by addition of H₂O (30 mL) and extractedwith EtOAc (50 mL×3). The combined organic was washed with saturatedaqueous NaHCO₃ (50 mL) and saturated aqueous NaCl (50 mL), dried overMgSO₄, filtered and concentrated in vacuo. The residue was crystallizedin EtOH to afford 1.35 g of the title compound as a light beige solid asthe first crop. The second crop of the title product (0.44 g) was alsoisolated by concentrating the mother liquid followed byrecrystallization in EtOH. LC/MS (method B): retention time=2.03 min,[M+H]⁺=301.9.

56B. Preparation of 5-bromo-4-(4-chlorophenyl)-2-hydrazinylpyridine

To a solution of 5-bromo-2-chloro-4-(4-chlorophenyl)pyridine (1.3 g, 4.3mmol) in THF (10 mL) was added hydrazine (1.4 g, 43 mmol). The reactionmixture was refluxed under argon for 4 days, then allowed to cool to 20°C. and concentrated in vacuo. The residue was purified by using reversephase preparative HPLC (Conditions: Phenomenex Luna 5μC 18 30×100 mm;Eluted with 0% to 100% B, 10 min gradient, 100% B hold for 5 min, (A=90%H₂O, 10% CH₃CN, 0.1% trifluoroacetic acid and B=10% H₂O, 90% CH₃CN, 0.1%trifluoroacetic acid); Flow rate at 40 mL/min, UV detection at 220 nm),followed by basification with 1N aqueous NaOH to pH 12 and extractionwith CHCl₃ to afford 0.82 g (63%) of the title compound as an off-whitesolid. LC/MS (method B): retention time=1.47 min, [M+H]⁺=298.0.

56C. Preparation ofN′-(5-bromo-4-(4-chlorophenyl)pyridin-2-yl)-2-(6-(trifluoromethyl)pyridin-3-yl)acetohydrazide

To a suspension of 5-bromo-4-(4-chlorophenyl)-2-hydrazinylpyridine (37mg, 0.12 mmol), 2-(6-(trifluoromethyl)pyridin-3-yl)acetic acid (26 mg,0.12 mmol) and bromotripyrrolidinophosphonium hexafluorophosphate(PyBop, 70 mg, 0.13 mmol) in CH₃CN (1.0 mL) was added (i-Pr)₂EtN (32 mg,0.25 mmol) at 20° C. The reaction mixture was stirred at 20° C. underargon for 15 h, then concentrated in vacuo. The residue was dissolved inEtOAc (15 mL). The organic solution was successively washed withsaturated aqueous NaHCO₃ (5 mL) and saturated aqueous NaCl (5 mL), driedover MgSO₄, filtered and concentrated in vacuo. The residue was purifiedusing reverse phase preparative HPLC (Conditions: Phemomenex Luna 5μ C1830×75 mm; Eluted with 0% to 100% B, 10 min gradient, 100% B hold for 2min, (A=90% H₂O, 10% CH₃CN, 0.1% trifluoroacetic acid and B=10% H₂O, 90%CH₃CN, 0.1% trifluoroacetic acid); Flow rate at 40 mL/min, UV detectionat 220 nm), followed by basification with 1N aqueous NaOH to pH 12 andextraction with EtOAc to afford 54 mg (92%) of the title compound as awhite solid. LC/MS (method B): retention time=1.91 min, [M+H]⁺=487.0.

56D. Preparation of6-bromo-7-(4-chlorophenyl)-3-((6-(trifluoromethyl)pyridin-3-yl)methyl)-[1,2,4]triazolo[4,3-a]pyridine

To a suspension ofN′-(5-bromo-4-(4-chlorophenyl)pyridin-2-yl)-2-(6-(trifluoromethyl)pyridin-3-yl)acetohydrazide(24 mg, 0.05 mmol) in (trifluoromethyl)benzene (0.45 mL) was addedglacial acidic acid (0.15 mL). The reaction mixture was sealed andheated in a microwave reactor at 200° C. for 30 min. The reactionmixture was allowed to cool to 20° C. and concentrated in vacuo. Theresidue was purified using reverse phase preparative HPLC (Conditions:Phemomenex Luna 5μC18 30×75 mm; Eluted with 0% to 100% B, 10 mingradient, 100% B hold for 2 min, (A=90% H₂O, 10% CH₃CN, 0.1%trifluoroacetic acid and B=10% H₂O, 90% CH₃CN, 0.1% trifluoroaceticacid); Flow rate at 40 mL/min, UV detection at 220 nm) to afford 21 mg(90%) of the title compound as a white solid. LC/MS (method B):retention time=1.86 min, [M+H]⁺=467.0.

56E. Preparation of7-(4-chlorophenyl)-6-(2,4-dichlorophenyl)-3-((6-(trifluoromethyl)pyridin-3-yl)methyl)-[1,2,4]triazolo[4,3-a]pyridine

To a degassed solution of6-bromo-7-(4-chlorophenyl)-3-((6-(trifluoromethyl)pyridin-3-yl)methyl)-[1,2,4]triazolo[4,3-a]pyridine(9.5 mg, 0.02 mmol), 2,4-dichlorophenylboronic acid (8.0 mg, 0.041 mmol)and K₂CO₃ (8.5 mg, 0.061 mmol) in 1,4-dioxane (0.3 mL) and H₂O (0.1 mL)was added Pd(PPh₃)₄ (2.3 mg, 0.002 mmol) under argon at 20° C. Thereaction mixture was heated at 100° C. for 2 h under argon, then allowedto cool to 20° C. The reaction was concentrated in vacuo, and theresidue was purified using reverse phase preparative HPLC (Conditions:Phemomenex Luna 5μC18 30×75 mm; Eluted with 0% to 100% B, 10 mingradient, 100% B hold for 2 min, (A=90% H₂O, 10% CH₃CN, 0.1%trifluoroacetic acid and B=10% H₂O, 90% CH₃CN, 0.1% trifluoroaceticacid); Flow rate at 40 mL/min, UV detection at 220 nm) to afford 5.5 mg(55%) of the title compound as a white solid. LC/MS (method B):retention time=2.03 min, [M+H]⁺=533.2.

Example 57 Preparation of7-(4-chlorophenyl)-6-(2,4-dichlorophenyl)-3-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-[1,2,4]triazolo[4,3-a]pyridine

57A. Preparation ofN′-(5-bromo-4-(4-chlorophenyl)pyridin-2-yl)-2-(2-methyl-6-(trifluoromethyl)pyridin-3-yl)acetohydrazide

The title compound (160 mg, 97%) as a beige powder was prepared from5-bromo-4-(4-chlorophenyl)-2-hydrazinylpyridine (100 mg, 0.33 mmol),2-(2-methyl-6-(trifluoromethyl)pyridin-3-yl)acetic acid (75 mg, 0.33mmol), (i-Pr)₂EtN (86 mg, 0.66 mmol) and bromotripyrrolidinophosphoniumhexafluorophosphate (PyBop, 190 mg, 0.37 mmol) in CH₃CN (2.5 mL) by theprocedures analogous to those described forN′-(5-bromo-4-(4-chlorophenyl)pyridin-2-yl)-2-(6-(trifluoromethyl)pyridin-3-yl)acetohydrazide(Example 56C). LC/MS (method B): retention time=1.92 min, [M+H]⁺=499.0.

57B. Preparation of6-bromo-7-(4-chlorophenyl)-3-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-[1,2,4]triazolo[4,3-a]pyridine

The title compound (61 mg, 60%) as a white powder was prepared fromN′-(5-bromo-4-(4-chlorophenyl)pyridin-2-yl)-2-(2-methyl-6-(trifluoromethyl)pyridin-3-yl)acetohydrazide(100 mg, 0.20 mmol) in glacial acetic acid (0.6 mL) and(trifluoromethyl)benzene (1.8 mL) by the procedures analogous to thosedescribed for6-bromo-7-(4-chlorophenyl)-3-((6-(trifluoromethyl)pyridin-3-yl)methyl)-[1,2,4]triazolo[4,3-a]pyridine(Example 56D). LC/MS (method B): retention time=1.83 min, [M+H]⁺=481.0.

57C. Preparation of7-(4-chlorophenyl)-6-(2,4-dichlorophenyl)-3-((2-methyl-6(trifluoromethyl)pyridin-3-yl)methyl)-[1,2,4]triazolo[4,3-a]pyridine

The title compound (5.5 mg, 50%) as a white powder was prepared from6-bromo-7-(4-chlorophenyl)-3-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-[1,2,4]triazolo[4,3-a]pyridine(9.5 mg, 0.020 mmol), 2,4-dichlorophenylboronic acid (7.5 mg, 0.039mmol), K₂CO₃ (8.2 mg, 0.059 mmol) and Pd(PPh₃)₄ (2.8 mg, 0.002 mmol) in1,4-dioxane (0.28 mL) and H₂O (0.09 mL) by the procedures analogous tothose described for7-(4-chlorophenyl)-6-(2,4-dichlorophenyl)-3-((6-(trifluoromethyl)pyridin-3-yl)methyl)-[1,2,4]triazolo[4,3-a]pyridine(Example 56E). LC/MS (method B): retention time =2.04 min, [M+H]⁺=547.2.

Example 58 Preparation of7-(4-chlorophenyl)-6-(2-fluorophenyl)-3-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-[1,2,4]triazolo[4,3-a]pyridine

The title compound (5.5 mg, 55%) as a white powder was prepared from6-bromo-7-(4-chlorophenyl)-3-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-[1,2,4]triazolo[4,3-a]pyridine(9.5 mg, 0.020 mmol), 2-fluorophenylboronic acid (5.5 mg, 0.039 mmol),K₂CO₃ (8.2 mg, 0.059 mmol) and Pd(PPh₃)₄ (2.8 mg, 0.002 mmol) in1,4-dioxane (0.28 mL) and H₂O (0.09 mL) by the procedures analogous tothose described for7-(4-chlorophenyl)-6-(2,4-dichlorophenyl)-3-((6-(trifluoromethyl)pyridin-3-yl)methyl)-[1,2,4]triazolo[4,3-a]pyridine(Example 56E). LC/MS (method B): retention time=Time: 1.86,[M+H]⁺=497.3.

Example 59 Preparation of7-(4-chlorophenyl)-6-(2-methoxyphenyl)-3-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-[1,2,4]triazolo[4,3-a]pyridine

The title compound (7.7 mg, 75%) as a white powder was prepared from6-bromo-7-(4-chlorophenyl)-3-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-[1,2,4]triazolo[4,3-a]pyridine(9.5 mg, 0.020 mmol), 2-methoxyphenylboronic acid (6.0 mg, 0.039 mmol),K₂CO₃ (8.2 mg, 0.059 mmol) and Pd(PPh₃)₄ (2.8mg, 0.002 mmol) in1,4-dioxane (0.28 mL) and H₂O (0.09 mL) by the procedures analogous tothose described for7-(4-chlorophenyl)-6-(2,4-dichlorophenyl)-3-((6-(trifluoromethyl)pyridin-3-yl)methyl)-[1,2,4]triazolo[4,3-a]pyridine(Example 56E). LC/MS (method B): retention time=1.87 min, [M+H]⁺=509.3.

Example 60 Preparation of7-(4-chlorophenyl)-6-(2-chloro-4-methylphenyl)-3-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-[1,2,4]triazolo[4,3-a]pyridine

The title compound (6.5 mg, 60%) as a white powder was prepared from6-bromo-7-(4-chlorophenyl)-3-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-[1,2,4]triazolo[4,3-a]pyridine(9.5 mg, 0.020 mmol), 2-chloro-4-methylphenylboronic acid (6.7 mg, 0.039mmol), K₂CO₃ (8.2 mg, 0.059 mmol) and Pd(PPh₃)₄ (2.8 mg, 0.002 mmol) in1,4-dioxane (0.28 mL) and H₂O (0.09 mL) by the procedures analogous tothose described for7-(4-chlorophenyl)-6-(2,4-dichlorophenyl)-3-((6-(trifluoromethyl)pyridin-3-yl)methyl)-[1,2,4]triazolo[4,3-a]pyridine(Example 56E). LC/MS (method B): retention time=2.01 min, [M+H]⁺=527.3.

Example 61 Preparation of7-(4-chlorophenyl)-3-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-6-o-tolyl-[1,2,4]triazolo[4,3-a]pyridine

The title compound (6.3 mg, 65%) as a white powder was prepared from6-bromo-7-(4-chlorophenyl)-3-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-[1,2,4]triazolo[4,3-a]pyridine(9.5 mg, 0.020 mmol), 2-methylphenylboronic acid (5.4 mg, 0.039 mmol),K₂CO₃ (8.2 mg, 0.059 mmol) and Pd(PPh₃)₄ (2.8 mg, 0.002 mmol) in1,4-dioxane (0.28 mL) and H₂O (0.09 mL) by the procedures analogous tothose described for7-(4-chlorophenyl)-6-(2,4-dichlorophenyl)-3-((6-(trifluoromethyl)pyridin-3-yl)methyl)-[1,2,4]triazolo[4,3-a]pyridine(Example 56E). LC/MS (method B): retention time=1.97 min, [M+H]⁺=543.3.

Example 62 Preparation of7-(4-chlorophenyl)-6-(2,4-dimethylphenyl)-3-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-[1,2,4]triazolo[4,3-a]pyridine

The title compound (6.5 mg, 65%) as a white powder was prepared from6-bromo-7-(4-chlorophenyl)-3-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-[1,2,4]triazolo[4,3-a]pyridine(9.5 mg, 0.020 mmol), 2,4-dimethylphenylboronic acid (5.9 mg, 0.039mmol), K₂CO₃ (8.2 mg, 0.059 mmol) and Pd(PPh₃)₄ (2.8 mg, 0.002 mmol) in1,4-dioxane (0.28 mL) and H₂O (0.09 mL) by the procedures analogous tothose described for7-(4-chlorophenyl)-6-(2,4-dichlorophenyl)-3-((6-(trifluoromethyl)pyridin-3-yl)methyl)-[1,2,4]triazolo[4,3-a]pyridine(Example 56E). LC/MS (method B): retention time=2.00 min, [M+H]⁺=507.3.

Example 63 Preparation of6-(2-chloro-4-methoxyphenyl)-7-(4-chlorophenyl)-3-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-[1,2,4]triazolo[4,3-a]pyridine

The title compound (7.5 mg, 70%) as a white powder was prepared from6-bromo-7-(4-chlorophenyl)-3-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-[1,2,4]triazolo[4,3-a]pyridine(9.5 mg, 0.020 mmol), 2-chloro-4-methoxyphenyl-boronic acid (7.3 mg,0.039 mmol), K₂CO₃ (8.2 mg, 0.059 mmol) and Pd(PPh₃)₄ (2.8 mg, 0.002mmol) in 1,4-dioxane (0.28 mL) and H₂O (0.09 mL) by the proceduresanalogous to those described for7-(4-chlorophenyl)-6-(2,4-dichlorophenyl)-3-((6-(trifluoromethyl)pyridin-3-yl)methyl)-[1,2,4]triazolo[4,3-a]pyridine(Example 56E). LC/MS (method B): retention time=1.97 min [M+H]⁺=543.3.

Example 64 Preparation of6-(2-chlorophenyl)-7-(4-chlorophenyl)-3-(2,2,2-trifluoroethoxy)-[1,2,4]triazolo[4,3-a]pyridine

64A. Preparation of6-(2-chlorophenyl)-7-(4-chlorophenyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one

The title compound (190 mg, 88% yield) as a yellow foam was preparedfrom 5-(2-chlorophenyl)-4-(4-chlorophenyl)-2-hydrazinylpyridine (200 mg,0.61 mmol) in a manner analogous to that in which6-(2-chlorophenyl)-7-(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one(Example 1G) was prepared. HPLC/MS:retention time=3.83 min,[M+H]⁺=356.1.

64B. Preparation of3-chloro-6-(2-chlorophenyl)-7-(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridine

The title compound (100 mg, 56% yield) as a white solid was preparedfrom6-(2-chlorophenyl)-7-(4-chlorophenyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one(170 mg, 0.48 mmol) in a manner analogous to that in which3-chloro-6-(2-chlorophenyl)-7-(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazine(Example 1H) was prepared. HPLC/MS: retention time=3.87 min,[M+H]⁺=374.0.

64C. Preparation of6-(2-chlorophenyl)-7-(4-chlorophenyl)-3-(2,2,2-trifluoroethoxy)-[1,2,4]triazolo[4,3-a]pyridine

The title compound (21 mg, 48% yield) as a white powder was preparedfrom3-chloro-6-(2-chlorophenyl)-7-(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridine(38 mg, 0.1 mmol), 2,2,2-trifluoroethanol (72 μL, 1.0 mmol),2-tert-butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diazaphosphorine(144 μL, 0.5 mmol) and anhydrous THF (0.5 mL)in a manner analogous tothat in which6-(2-chlorophenyl)-7-(4-chlorophenyl)-3-(2,2,2-trifluoroethoxy)-[1,2,4]triazolo[4,3-a]pyridazine(Example 6) was prepared. HPLC/MS: retention time=3.86 min,[M+H]⁺=438.1.

Biological Evaluation

Cannabinoid Receptor Binding Assay

Radioligand binding studies were conducted in membranes prepared fromChinese Hamster Ovary (CHO) cells that over-express recombinant humanCB-1 (CHO—CB-1 cells). Total assay volume for the binding studies was100 μl. 5 μg of membranes were brought up to a final volume of 95 μlwith Binding Buffer (25 mM HEPES, 150 mM NaCl, 2.5 mM CaCl₂, 1 mM MgCl₂,0.25% BSA). The diluted membranes were preincubated with a compound orDMSO vehicle. The binding reaction was initiated by the addition of 2 nMfinal ³H-CP-55,940 (120 Ci/mmol) and proceeded for 2.5 hours at roomtemperature. The binding reaction was terminated by transferring thereaction to GF/B 96 well plates (presoaked with 0.3% polyethylenimine)using a Packard Cell Harvester. The filter was washed with 0.25×PBS, 30μl MicroScint was added per well, and the bound radiolabel wasquantitated by scintillation counting on a Packard TopCountScintillation Counter. The CB-2 radioligand binding assay was conductedidentically except that the membranes from CHO—CB-2 cells were used.

For a compound to be considered a CB-1 antagonist, the compound mustpossess a CB-1 receptor binding affinity Ki less than 13000 nM. Asdetermined by the assay described above, the CB-1 receptor binding K_(i)values of working Examples 1-63 fall within the range of 0.01 nM to10000 nM.

Cannabinoid Receptor Functional Activity Assay

Functional CB-1 inverse agonist activity of test compounds wasdetermined in CHO—CB-1 cells using a cAMP accumulation assay. CHO—CB-1cells were grown in 96 well plates to near confluence. On the day of thefunctional assay, growth medium was aspirated and 100 of Assay Buffer(PBS plus 25 mM HEPES/0.1 mM 3-isobutyl-1-methylxanthine/0.1% BSA) wasadded. Compounds were added to the Assay buffer diluted 1:100 from 100%DMSO and allowed to preincubate for 10 minutes prior to addition of 5 uMforskolin. The mixture was allowed to proceed for 15 minutes at roomtemperature and was terminated by the addition of 0.1 N HCl. The totalintracellular cAMP concentration was quantitated using the Amersham cAMPSPA kit.

Utilities And Combinations

Utilities

The compounds of the present invention are cannabinoid receptormodulators, and include compounds which are, for example, selectiveagonists, partial agonists, inverse agonists, antagonists or partialantagonists of the cannabinoid receptor. Accordingly, the compounds ofthe present invention may be useful for the treatment or prevention ofdiseases and disorders associated with G-protein coupled cannabinoidreceptor activity. Preferably, compounds of the present inventionpossess activity as antagonists or inverse agonists of the CB-1receptor, and may be used in the treatment of diseases or disordersassociated with the activity of the CB-1 receptor.

Accordingly, the compounds of the present invention can be administeredto mammals, preferably humans, for the treatment of a variety ofconditions and disorders, including, but not limited to metabolic andeating disorders as well as conditions associated with metabolicdisorders, (e.g., obesity, diabetes, arteriosclerosis, hypertension,polycystic ovary disease, cardiovascular disease, osteoarthritis,dermatological disorders, hypertension, insulin resistance,hypercholesterolemia, hypertriglyceridemia, cholelithiasis and sleepdisorders, hyperlipidemic conditions, bulimia nervosa and compulsiveeating disorders) or psychiatric disorders, such as substance abuse,depression, anxiety, mania and schizophrenia. These compounds could alsobe used for the improvement of cognitive function (e.g., the treatmentof dementia, including Alzheimer's disease, short term memory loss andattention deficit disorders); neurodegenerative disorders (e.g.,Parkinson's Disease, cerebral apoplexy and craniocerebral trauma) andhypotension (e.g., hemorrhagic and endotoxin-inducd hypotension). Thesecompounds could also be used for treatment of catabolism in connectionwith pulmonary dysfunction and ventilator dependency; treatment ofcardiac dysfunction (e.g., associated with valvular disease, myocardialinfarction, cardiac hypertrophy or congestive heart failure); andimprovement of the overall pulmonary function; transplant rejection;rheumatoid arthritis; multiple sclerosis; inflammatory bowel disease;lupus; graft vs. host disease; T-cell mediated hypersensitivity disease;psoriasis; asthma; Hashimoto's thyroiditis; Guillain-Barre syndrome;cancer; contact dermatitis; allergic rhinitis; and ischemic orreperfusion injury.

Compounds useful in the treatment of appetitive or motivationaldisorders regulate desires to consume sugars, carbohydrates, alcohol ordrugs and more generally to regulate the consumption of ingredients withhedonic value. In the present description and in the claims, appetitivedisorders are understood as meaning:disorders associated with asubstance and especially abuse of a substance and/or dependency on asubstance, disorders of eating behaviors, especially those liable tocause excess weight, irrespective of its origin, for example: bulimianervosa, craving for sugars. The present invention therefore furtherrelates to the use of a CB-1 receptor antagonist or inverse agonist forthe treatment of bulimia and obesity, including obesity associated withtype II diabetes (non-insulin-dependent diabetes), or more generally anydisease resulting in the patient becoming overweight. Obesity, asdescribed herein, is defined by a body mass index (kg/m²) of at least26. It may be due to any cause, whether genetic or environmental,including overeating and bulemia, polycycstic ovary disease,craniopharyngeoma, Prader-Willi Syndrome, Frohlich's Syndrome, Type IIdiabetes, growth hormone deficiency, Turner's Syndrome and otherpathological states characterized by reduced metabolic activity orreduced energy expenditure. As used with reference to the utilitiesdescribed herein, the term “treating” or “treatment” encompassesprevention, partial alleviation, or cure of the disease or disorder.Further, treatment of obesity is expected to prevent progression ofmedical covariants of obesity, such as arteriosclerosis, Type IIdiabetes, polycystic ovary disease, cardiovascular disease,osteoarthritis, dermatological disorders, hypertension, insulinresistance, hypercholesterolemia, hypertriglyceridemia, cholelithiasisand sleep disorders.

Compounds in the present invention may also be useful in treatingsubstance abuse disorders, including substance dependence or abusewithout physiological dependence. Substances of abuse include alcohol,amphetamines (or amphetamine-like substances), caffeine, cannabis,cocaine, hallucinogens, inhalents, nicotine, opioids, phencyclidine (orphencyclidine-like compounds), sedative-hypnotics or benzodiazepines,and other (or unknown) substances and combinations of the above. Theterms “substance abuse disorders” also includes drug or alcoholwithdrawal syndromes and substance-induced anxiety or mood disorder withonset during withdrawal.

Compounds in the present invention may be useful in treating memoryimpairment and cognitive disorders. The condition of memory impairmentis manifested by impairment of the ability to learn new informationand/or the inability to recall previously learned information. Memoryimpairment is a primary symptom of dementia and can also be a symptomassociated with such diseases as Alzheimer's disease, schizophrenia,Parkinson's disease, Huntington's disease, Pick's disease,Creutzfeld-Jakob disease, HIV, cardiovascular disease, and head traumaas well as age-related cognitive decline. Dementias are diseases thatinclude memory loss and additional intellectual impairment separate frommemory. Cannabinoid receptor modulators may also be useful in treatingcognitive impairments related to attentional deficits, such as attentiondeficit disorder.

Compounds in the present invention may also be useful in treatingdiseases associated with dysfunction of brain dopaminergic systems, suchas Parkinson's Disease and substance abuse disorders. Parkinsons'sDisease is a neurodenerative movement disorder characterized bybradykinesia and tremor.

As modulators of the cannabinoid receptor, the compounds of the presentinvention are further useful for the treatment and prevention ofrespiratory diseases and disorders. Respiratory diseases for whichcannabinoid receptor modulators are useful include, but are not limitedto, chronic pulmonary obstructive disorder, emphysema, asthma, andbronchitis. In addition, cannabinoid receptor modulators block theactivation of lung epithelial cells by moeties such as allergic agents,inflammatory cytokines or smoke, thereby limiting release of mucin,cytokines, and chemokines, or selectively inhibiting lung epithelialcell activation.

Moreover, the compounds employed in the present invention may stimulateinhibitory pathways in cells, particularly in leukocytes, lungepithelial cells, or both, and are thus useful in treating suchdiseases. “Leukocyte activation” is defined herein as any or all of cellproliferation, cytokine production, adhesion protein expression, andproduction of inflammatory mediators. “Epithelial cell activation” isdefined herein as the production of any or all of mucins, cytokines,chemokines, and adhesion protein expression.

Use of the compounds of the present invention for treating leukocyteactivation-associated disorders is exemplified by, but is not limitedto, treating a range of disorders such as: transplant (such as organtransplant, acute transplant, xenotransplant or heterograft or homograft(such as is employed in bum treatment)) rejection; protection fromischemic or reperfusion injury such as ischemic or reperfusion injuryincurred during organ transplantation, myocardial infarction, stroke orother causes; transplantation tolerance induction; arthritis (such asrheumatoid arthritis, psoriatic arthritis or osteoarthritis); multiplesclerosis; respiratory and pulmonary diseases including but not limitedto chronic obstructive pulmonary disease (COPD), emphysema, bronchitis,and acute respiratory distress syndrome (ARDS); inflammatory boweldisease, including ulcerative colitis and Crohn's disease; lupus(systemic lupus erythematosis); graft vs. host disease; T-cell mediatedhypersensitivity diseases, including contact hypersensitivity,delayed-type hypersensitivity, and gluten-sensitive enteropathy (Celiacdisease); psoriasis; contact dermatitis (including that due to poisonivy); Hashimoto's thyroiditis; Sjogren's syndrome; AutoimmuneHyperthyroidism, such as Graves' Disease; Addison's disease (autoimmunedisease of the adrenal glands); Autoimmune polyglandular disease (alsoknown as autoimmune polyglandular syndrome); autoimmune alopecia;pernicious anemia; vitiligo; autoimmune hypopituatarism; Guillain-Barresyndrome; other autoimmune diseases; glomerulonephritis; serum sickness;uticaria; allergic diseases such as respiratory allergies (asthma,hayfever, allergic rhinitis) or skin allergies; scleracierma; mycosisfungoides; acute inflammatory and respiratory responses (such as acuterespiratory distress syndrome and ishchemia/reperfusion injury);dermatomyositis; alopecia areata; chronic actinic dermatitis; eczema;Behcet's disease; Pustulosis palmoplanteris; Pyoderma gangrenum;Sezary's syndrome; atopic dermatitis; systemic schlerosis; and morphea.The term “leukocyte activation-associated” or “leukocyte-activationmediated” disease as used herein includes each of the above referenceddiseases or disorders. In a particular embodiment, the compounds of thepresent invention are useful for treating the aforementioned exemplarydisorders irrespective of their etiology. The combined activity of thepresent compounds towards monocytes, macrophages, T-cells, etc. may beuseful in treating any of the above-mentioned disorders.

Cannabinoid receptors are important in the regulation of Fc gammareceptor responses of monocytes and macrophages. Compounds of thepresent invention inhibit the Fc gamma dependent production of TNF alphain human monocytes/macrophages. The ability to inhibit Fc gamma receptordependent monocyte and macrophage responses results in additionalanti-inflammatory activity for the present compounds. This activity isespecially of value, for example, in treating inflammatory diseases suchas arthritis or inflammatory bowel disease. In particular, the presentcompounds are useful for treating autoimmune glomerulonephritis andother instances of glomerulonephritis induced by deposition of immunecomplexes in the kidney that trigger Fc gamma receptor responses leadingto kidney damage.

Cannabinoid receptors are expressed on lung epithelial cells. Thesecells are responsible for the secretion of mucins and inflammatorycytokines/chemokines in the lung and are thus intricately involved inthe generation and progression of respiratory diseases. Cannabinoidreceptor modulators regulate both the spontaneous and the stimulatedproduction of both mucins and cytokines. Thus, such compounds are usefulin treating respiratory and pulmonary diseases including, COPD, ARDS,and bronchitis.

Further, cannabinoid receptors may be expressed on gut epithelial cellsand hence regulate cytokine and mucin production and may be of clinicaluse in treating inflammatory diseases related to the gut. Cannabinoidreceptors are also expressed on lymphocytes, a subset of leukocytes.Thus, cannabinoid receptor modulators will inhibit B and T-cellactivation, proliferation and differentiation. Thus, such compounds willbe useful in treating autoimmune diseases that involve either antibodyor cell mediated responses such as multiple sclerosis and lupus.

In addition, cannabinoid receptors regulate the Fc epsilon receptor andchemokine induced degranulation of mast cells and basophils. These playimportant roles in asthma, allergic rhinitis, and other allergicdisease. Fc epsilon receptors are stimulated by IgE-antigen complexes.Compounds of the present invention inhibit the Fc epsilon induceddegranulation responses, including the basophil cell line, RBL. Theability to inhibit Fc epsilon receptor dependent mast cell and basophilresponses results in additional anti-inflammatory and anti-allergicactivity for the present compounds. In particular, the present compoundsare useful for treating asthma, allergic rhinitis, and other instancesof allergic disease.

Combinations

The present invention includes within its scope pharmaceuticalcompositions comprising, as an active ingredient, a therapeuticallyeffective amount of at least one of the compounds of formula I, alone orin combination with a pharmaceutical carrier or diluent. Optionally,compounds of the present invention can be used alone, in combinationwith other suitable therapeutic agents useful in the treatment of theaforementioned disorders including: anti-obesity agents; anti-diabeticagents, appetite suppressants; cholesterol/lipid-lowering agents,HDL-raising agents, cognition enhancing agents, agents used to treatneurodegeneration, agents used to treat respiratory conditions, agentsused to treat bowel disorders, anti-inflammatory agents; anti-anxietyagents; anti-depressants; anti-hypertensive agents; cardiac glycosides;and anti-tumor agents.

Such other therapeutic agent(s) may be administered prior to,simultaneously with, or following the administration of the cannabinoidreceptor modulators in accordance with the invention.

Examples of suitable anti-obesity agents for use in combination with thecompounds of the present invention include melanocortin receptor (MC4R)agonists, melanin-concentrating hormone receptor (MCHR) antagonists,growth hormone secretagogue receptor (GHSR) antagonists, galaninreceptor modulators, orexin antagonists, CCK agonists, GLP-1 agonists,and other Pre-proglucagon-derived peptides; NPY1 or NPY5 antagonsist,NPY2 and NPY4 modulators, corticotropin releasing factor agonists,histamine receptor-3 (H3) modulators, aP2 inhibitors, PPAR gammamodulators, PPAR delta modulators, acetyl-CoA carboxylase (ACC)inihibitors, 11-β-HSD-1 inhibitors, adinopectin receptor modulators;beta 3 adrenergic agonists, such as AJ9677 (Takeda/Dainippon), L750355(Merck), or CP331648 (Pfizer) or other known beta 3 agonists asdisclosed in U.S. Pat. Nos. 5,541,204, 5,770,615, 5,491,134, 5,776,983and 5,488,064, a thyroid receptor beta modulator, such as a thyroidreceptor ligand as disclosed in WO 97/21993 (U. Cal SF), WO 99/00353(KaroBio) and WO 00/039077 (KaroBio), a lipase inhibitor, such asorlistat or ATL-962 (Alizyme), serotonin receptor agonists, (e.g.,BVT-933 (Biovitrum)), monoamine reuptake inhibitors or releasing agents,such as fenfluramine, dexfenfluramine, fluvoxamine, fluoxetine,paroxetine, sertraline, chlorphentermine, cloforex, clortermine,picilorex, sibutramine, dexamphetamine, phentermine, phenylpropanolamineor mazindol, anorectic agents such as topiramate (Johnson & Johnson),CNTF (ciliary neurotrophic factor)/Axokine® (Regeneron), BDNF(brain-derived neurotrophic factor), leptin and leptin receptormodulators, or cannabinoid-1 receptor antagonists, such as SR-141716(Sanofi) or SLV-319 (Solvay).

Examples of suitable anti-diabetic agents for use in combination withthe compounds of the present invention include: insulin secretagogues orinsulin sensitizers, which may include biguanides, sulfonyl ureas,glucosidase inhibitors, aldose reductase inhibitors, PPAR γ agonistssuch as thiazolidinediones, PPAR α agonists (such as fibric acidderivatives), PPAR δ antagonists or agonists, PPAR α/γ dual agonists,11-β-HSD-1 inhibitors, dipeptidyl peptidase IV (DP4) inhibitors, SGLT2inhibitors, glycogen phosphorylase inhibitors, and/or meglitinides, aswell as insulin, and/or glucagon-like peptide-1 (GLP-1), GLP-1 agonist,and/or a PTP-1B inhibitor (protein tyrosine phosphatase-1B inhibitor).

The antidiabetic agent may be an oral antihyperglycemic agent preferablya biguanide such as metformin or phenformin or salts thereof, preferablymetformin HCl. Where the antidiabetic agent is a biguanide, thecompounds of the present invention will be employed in a weight ratio tobiguanide within the range from about 0.001:1 to about 10:1, preferablyfrom about 0.01:1 to about 5:1.

The antidiabetic agent may also preferably be a sulfonyl urea such asglyburide (also known as glibenclamide), glimepiride (disclosed in U.S.Pat. No. 4,379,785), glipizide, gliclazide or chlorpropamide, otherknown sulfonylureas or other antihyperglycemic agents which act on theATP-dependent channel of the beta-cells, with glyburide and glipizidebeing preferred, which may be administered in the same or in separateoral dosage forms. The oral antidiabetic agent may also be a glucosidaseinhibitor such as acarbose (disclosed in U.S. Pat. No. 4,904,769) ormiglitol (disclosed in U.S. Pat. No. 4,639,436), which may beadministered in the same or in a separate oral dosage forms.

The compounds of the present invention may be employed in combinationwith a PPAR γ agonist such as a thiazolidinedione oral anti-diabeticagent or other insulin sensitizers (which has an insulin sensitivityeffect in NIDDM patients) such as rosiglitazone (SKB), pioglitazone(Takeda), Mitsubishi's MCC-555 (disclosed in U.S. Pat. No. 5,594,016),Glaxo-Wellcome's GL-262570, englitazone (CP-68722, Pfizer) ordarglitazone (CP-86325, Pfizer, isaglitazone (MIT/J&J), JTT-501(JPNT/P&U), L-895645 (Merck), R-1 19702 (Sankyo/WL), NN-2344 (Dr.Reddy/NN), or YM-440 (Yamanouchi), preferably rosiglitazone andpioglitazone.

The compounds of the present invention may be employed with a PPARα/γdual agonist such as MK-767/KRP-297 (Merck/Kyorin; as described in, K.Yajima, et. al., Am. J. Physiol. Endocrinol. Metab., 284: E966-E971(2003)), AZ-242 (tesaglitazar; Astra-Zeneca; as described in B. Ljung,et. al., J. Lipid Res., 43, 1855-1863(2002)); muraglitazar; or thecompounds described in U.S. Pat. 6,414,002.

The compounds of the present invention may be employed in combinationwith anti-hyperlipidemia agents, or agents used to treatarteriosclerosis. An example of an hypolipidemic agent would be an HMGCoA reductase inhibitor which includes, but is not limited to,mevastatin and related compounds as disclosed in U.S. Pat. No.3,983,140, lovastatin (mevinolin) and related compounds as disclosed inU.S. Pat. No. 4,231,938, pravastatin and related compounds such asdisclosed in U.S. Pat. No. 4,346,227, simvastatin and related compoundsas disclosed in U.S. Pat. Nos. 4,448,784 and 4,450,171. Other HMG CoAreductase inhibitors which may be employed herein include, but are notlimited to, fluvastatin, disclosed in U.S. Pat. No. 5,354,772,cerivastatin disclosed in U.S. Pat. Nos. 5,006,530 and 5,177,080,atorvastatin disclosed in U.S. Pat. Nos. 4,681,893, 5,273,995, 5,385,929and 5,686,104, pitavastatin (Nissan/Sankyo's nisvastatin (NK-104) oritavastatin), disclosed in U.S. Pat. No. 5,011,930,Shionogi-Astra/Zeneca rosuvastatin (visastatin (ZD-4522)) disclosed inU.S. Pat. No. 5,260,440, and related statin compounds disclosed in U.S.Pat. No. 5,753,675, pyrazole analogs of mevalonolactone derivatives asdisclosed in U.S. Pat. No. 4,613,610, indene analogs of mevalonolactonederivatives as disclosed in PCT application WO 86/03488,6-[2-(substituted-pyrrol-1-yl)-alkyl)pyran-2-ones and derivativesthereof as disclosed in U.S. Pat. No. 4,647,576, Searle's SC-45355 (a3-substituted pentanedioic acid derivative) dichloroacetate, imidazoleanalogs of mevalonolactone as disclosed in PCT application WO 86/07054,3-carboxy-2-hydroxy-propane-phosphonic acid derivatives as disclosed inFrench Patent No. 2,596,393, 2,3-disubstituted pyrrole, furan andthiophene derivatives as disclosed in European Patent Application No.0221025, naphthyl analogs of mevalonolactone as disclosed in U.S. Pat.No. 4,686,237, octahydronaphthalenes such as disclosed in U.S. Pat. No.4,499,289, keto analogs of mevinolin (lovastatin) as disclosed inEuropean Patent Application No.0,142,146 A2, and quinoline and pyridinederivatives disclosed in U.S. Pat. Nos. 5,506,219 and 5,691,322. Inaddition, phosphinic acid compounds useful in inhibiting HMG CoAreductase suitable for use herein are disclosed in GB 2205837.

The squalene synthetase inhibitors suitable for use herein include, butare not limited to, α-phosphono-sulfonates disclosed in U.S. Pat. No.5,712,396, those disclosed by Biller, et al., J Med. Chem., 31,1869-1871 (1998) including isoprenoid (phosphinyl-methyl)phosphonates aswell as other known squalene synthetase inhibitors, for example, asdisclosed in U.S. Pat. No. 4,871,721 and 4,924,024 and in Biller, S. A.,Neuenschwander, K., Ponpipom, M. M., and Poulter, C. D., CurrentPharmaceutical Design, 2, 1-40 (1996).

In addition, other squalene synthetase inhibitors suitable for useherein include the terpenoid pyrophosphates disclosed by P. Ortiz deMontellano, et al., J. Med. Chem., 20, 243-249 (1977), the famesyldiphosphate analog A and presqualene pyrophosphate (PSQ-PP) analogs asdisclosed by Corey and Volante, J. Am. Chem. Soc., 98, 1291-1293 (1976),phosphinylphosphonates reported by McClard, R. W. et al., J. Am. Chem.Soc., 109, 5544 (1987) and cyclopropanes reported by Capson, T. L., PhDdissertation, Jun., 1987, Dept. Med. Chem. U of Utah, Abstract, Table ofContents, pp 16, 17, 40-43, 48-51, Summary.

Other hypolipidemic agents suitable for use herein include, but are notlimited to, fibric acid derivatives, such as fenofibrate, gemfibrozil,clofibrate, bezafibrate, ciprofibrate, clinofibrate and the like,probucol, and related compounds as disclosed in U.S. Pat. No. 3,674,836,probucol and gemfibrozil being preferred, bile acid sequestrants such ascholestyramine, colestipol and DEAE-Sephadex (SECHOLEX, POLICEXIDE) andcholestagel (Sankyo/Geltex), as well as lipostabil (Rhone-Poulenc),Eisai E-5050 (an N-substituted ethanolamine derivative), imanixil(HOE-402), tetrahydrolipstatin (THL), istigmastanylphos-phorylcholine(SPC, Roche), aminocyclodextrin (Tanabe Seiyoku), Ajinomoto AJ-814(azulene derivative), melinamide (Sumitomo), Sandoz 58-035, AmericanCyanamid CL-277,082 and CL-283,546 (disubstituted urea derivatives),nicotinic acid (niacin), acipimox, acifran, neomycin, p-aminosalicylicacid, aspirin, poly(diallylmethylamine) derivatives such as disclosed inU.S. Pat. No. 4,759,923, quaternary amine poly(diallyldimethylammoniumchloride) and ionenes such as disclosed in U.S. Pat. No. 4,027,009, andother known serum cholesterol lowering agents.

The other hypolipidemic agent may be an ACAT inhibitor (which also hasanti-atherosclerosis activity) such as disclosed in, Drugs of theFuture, 24, 9-15 (1999), (Avasimibe); “The ACAT inhibitor, C1-1011 iseffective in the prevention and regression of aortic fatty streak areain hamsters”, Nicolosi et al., Atherosclerosis (Shannon, Irel), 137 (1),77-85 (1998); “The pharmacological profile of FCE 27677: a novel ACATinhibitor with potent hypolipidemic activity mediated by selectivesuppression of the hepatic secretion of ApoB 100-containinglipoprotein”, Ghiselli, Giancarlo, Cardiovasc. Drug Rev., 16 (1), 16-30(1998); “RP 73163: abioavailable alkylsulfinyl-diphenylimidazole ACATinhibitor”, Smith, C., et al., Bioorg. Med. Chem. Lett, 6 (1), 47-50(1996); “ACAT inhibitors: physiologic mechanisms for hypolipidemic andanti-atherosclerotic activities in experimental animals”, Krause et al.,Editor(s): Ruffolo, Robert R., Jr.; Hollinger, Mannfred A.,Inflammation: Mediators Pathways, 173-98 (1995), Publisher: CRC, BocaRaton, Fla.; “ACAT inhibitors: potential anti-atherosclerotic agents”,Sliskovic et al., Curr. Med. Chem., 1 (3), 204-25 (1994); “Inhibitors ofacyl-CoA:cholesterol O-acyl transferase (ACAT) as hypocholesterolemicagents. 6. The first water-soluble ACAT inhibitor with lipid-regulatingactivity. Inhibitors of acyl-CoA:cholesterol acyltransferase (ACAT). 7.Development of a series of substitutedN-phenyl-N′-[(1-phenylcyclopentyl)-methyl]ureas with enhancedhypocholesterolemic activity”, Stout et al., Chemtracts: Org. Chem., 8(6), 359-62 (1995), or TS-962 (Taisho Pharmaceutical Co. Ltd), as wellas F-1394, CS-505, F-12511, HL-004, K-10085 and YIC-C8-434.

The hypolipidemic agent may be an upregulator of LDL receptor activitysuch as MD-700 (Taisho Pharmaceutical Co. Ltd) and LY295427 (Eli Lilly).The hypolipidemic agent may be a cholesterol absorption inhibitorpreferably Schering-Plough's SCH48461 (ezetimibe) as well as thosedisclosed in Atherosclerosis 115, 45-63 (1995) and J. Med. Chem. 41, 973(1998).

The other lipid agent or lipid-modulating agent may be a cholesteryltransfer protein inhibitor (CETP) such as Pfizer's CP-529,414 as well asthose disclosed in WO/0038722 and in EP 818448 (Bayer) and EP 992496,and Pharmacia's SC-744 and SC-795, as well as CETi-1 and JTT-705.

The hypolipidemic agent may be an ileal Na⁺/bile acid cotransporterinhibitor such as disclosed in Drugs of the Future, 24, 425-430 (1999).The ATP citrate lyase inhibitor which may be employed in the combinationof the invention may include, for example, those disclosed in U.S. Pat.No. 5,447,954.

The other lipid agent also includes a phytoestrogen compound such asdisclosed in WO 00/30665 including isolated soy bean protein, soyprotein concentrate or soy flour as well as an isoflavone such asgenistein, daidzein, glycitein or equol, or phytosterols, phytostanol ortocotrienol as disclosed in WO 2000/015201; a beta-lactam cholesterolabsorption inhibitor such as disclosed in EP 675714; an HDL upregulatorsuch as an LXR agonist, a PPAR α-agonist and/or an FXR agonist; an LDLcatabolism promoter such as disclosed in EP 1022272; a sodium-protonexchange inhibitor such as disclosed in DE 19622222; an LDL-receptorinducer or a steroidal glycoside such as disclosed in U.S. Pat. No.5,698,527 and GB 2304106; an anti-oxidant such as beta-carotene,ascorbic acid, α-tocopherol or retinol as disclosed in WO 94/15592 aswell as Vitamin C and an antihomocysteine agent such as folic acid, afolate, Vitamin B6, Vitamin B 12 and Vitamin E; isoniazid as disclosedin WO 97/35576; a cholesterol absorption inhibitor, an HMG-CoA synthaseinhibitor, or a lanosterol demethylase inhibitor as disclosed in WO97/48701; a PPAR δ agonist for treating dyslipidemia; or a sterolregulating element binding protein-I (SREBP-1) as disclosed in WO2000/050574, for example, a sphingolipid, such as ceramide, or neutralsphingomyelenase (N—SMase) or fragment thereof. Preferred hypolipidemicagents are pravastatin, lovastatin, simvastatin, atorvastatin,fluvastatin, pitavastatin and rosuvastatin, as well as niacin and/orcholestagel.

The compounds of the present invention may be employed in combinationwith anti-hypertensive agents. Examples of suitable anti-hypertensiveagents for use in combination with the compounds of the presentinvention include beta adrenergic blockers, calcium channel blockers(L-type and/or T-type; e.g. diltiazem, verapamil, nifedipine, amlodipineand mybefradil), diuretics (e.g., chlorothiazide, hydrochlorothiazide,flumethiazide, hydroflumethiazide, bendroflumethiazide,methylchlorothiazide, trichloromethiazide, polythiazide, benzthiazide,ethacrynic acid tricrynafen, chlorthalidone, furosemide, musolimine,bumetanide, triamtrenene, amiloride, spironolactone), renin inhibitors,ACE inhibitors (e.g., captopril, zofenopril, fosinopril, enalapril,ceranopril, cilazopril, delapril, pentopril, quinapril, ramipril,lisinopril), AT-1 receptor antagonists (e.g., losartan, irbesartan,valsartan), ET receptor antagonists (e.g., sitaxsentan, atrsentan andcompounds disclosed in U.S. Pat. Nos. 5,612,359 and 6,043,265), DualET/AII antagonist (e.g., compounds disclosed in WO 00/01389), neutralendopeptidase (NEP) inhibitors, vasopepsidase inhibitors (dual NEP-ACEinhibitors) (e.g., omapatrilat and gemopatrilat), and nitrates.

Cannbinoid receptor modulators could be useful in treating otherdiseases associated with obesity, including sleep disorders. Therefore,the compounds described in the present invention could be used incombination with therapeutics for treating sleep disorders. Examples ofsuitable therapies for treatment of sleeping disorders for use incombination with the compounds of the present invention includemelatonin analogs, melatonin receptor antagonists, ML 1 B agonists, GABAreceptor modulators; NMDA receptor modulators, histamine-3 (H3) receptormodulators, dopamine agonists and orexin receptor modulators.

Cannabinoid receptor modulators may reduce or ameliorate substance abuseor addictive disorders. Therefore, combination of cannabinoid receptormodulators with agents used to treat addictive disorders may reduce thedose requirement or improve the efficacy of current addictive disordertherapeutics. Examples of agents used to treat substance abuse oraddictive disorders are: selective serotonin reuptake inhibitors (SSRI),methadone, buprenorphine, nicotine and bupropion.

Cannabinoid receptor modulators may reduce anxiety or depression;

therefore, the compounds described in this application may be used incombination with anti-anxiety agents or antidepressants. Examples ofsuitable anti-anxiety agents for use in combination with the compoundsof the present invention include benzodiazepines (e.g., diazepam,lorazepam, oxazepam, alprazolam, chlordiazepoxide, clonazepam,chlorazepate, halazepam and prazepam), 5HT1A receptor agonists (e.g.,buspirone, flesinoxan, gepirone and ipsapirone), and corticotropinreleasing factor (CRF) antagonists.

Examples of suitable classes of anti-depressants for use in combinationwith the compounds of the present invention include norepinephrinereuptake inhibitors (tertiary and secondary amine tricyclics), selectiveserotonin reuptake inhibitors (SSRIs) (fluoxetine, fluvoxamine,paroxetine and sertraline), monoamine oxidase inhibitors (MAOIs)(isocarboxazid, phenelzine, tranylcypromine, selegiline), reversibleinhibitors of monoamine oxidase (RIMAs) (moclobemide), serotonin andnorepinephrine reuptake inhibitors (SNRIs) (venlafaxine), corticotropinreleasing factor (CRF) receptor antagonists, alpah-adrenoreceptorantagonists, and atypical antidepressants (bupropion, lithium,nefazodone, trazodone and viloxazine).

The combination of a conventional antipsychotic drug with a CB-1receptor antagonist could also enhance symptom reduction in thetreatment of psychosis or mania. Further, such a combination couldenable rapid symptom reduction, reducing the need for chronic treatmentwith antipsychotic agents. Such a combination could also reduce theeffective antipsychotic dose requirement, resulting in reducedprobability of developing the motor dysfunction typical of chronicantipsychotic treatment.

Examples of suitable antipsychotic agents for use in combination withthe compounds of the present invention include the phenothiazine(chlorpromazine, mesoridazine, thioridazine, acetophenazine,fluphenazine, perphenazine and trifluoperazine), thioxanthine(chlorprothixene, thiothixene), heterocyclic dibenzazepine (clozapine,olanzepine and aripiprazole), butyrophenone (haloperidol),dipheyylbutylpiperidine (pimozide) and indolone (molindolone) classes ofantipsychotic agents. Other antipsychotic agents with potentialtherapeutic value in combination with the compounds in the presentinvention include loxapine, sulpiride and risperidone.

Combination of the compounds in the present invention with conventionalantipsychotic drugs could also provide an enhanced therapeutic effectfor the treatment of schizophrenic disorders, as described above formanic disorders. As used here, schizophrenic disorders include paranoid,disorganized, catatonic, undifferentiated and residual schizophrenia,schizophreniform disorder, shcizoaffective disorder, delusionaldisorder, brief psychotic disorder and psychotic disorder not specified.Examples of suitable antipsychotic drugs for combination with thecompounds in the present invention include the antipsychotics mentionedabove, as well as dopamine receptor antagonists, muscarinic receptoragonists, 5HT2A receptor antagonists and 5HT2A/dopamine receptorantagonists or partial agonists (e.g., olanzepine, aripiprazole,risperidone, ziprasidone).

The compounds described in the present invention could be used toenhance the effects of cognition-enhancing agents, such asacetylcholinesterase inhibitors (e.g., tacrine), muscarinic receptor-lagonists (e.g., milameline), nicotinic agonists, glutamic acid receptor(AMPA and NMDA) modulators, and nootropic agents (e.g., piracetam,levetiracetam). Examples of suitable therapies for treatment ofAlzheimer's disease and cognitive disorders for use in combination withthe compounds of the present invention include donepezil, tacrine,revastigraine, 5HT6, gamma secretase inhibitors, beta secretaseinhibitors, SK channel blockers, Maxi-K blockers, and KCNQs blockers.

The compounds described in the present invention could be used toenhance the effects of agents used in the treatment of Parkinson'sDisease. Examples of agents used to treat Parkinson's Disease include:levadopa with or without a COMT inhibitor, antiglutamatergic drugs(amantadine, riluzole), alpha-2 adrenergic antagonists such as idazoxan,opiate antagonists, such as naltrexone, other dopamine agonists ortransportor modulators, such as ropinirole, or pramipexole orneurotrophic factors such as glial derived neurotrophic factor (GDNF).

The compounds described in the present invention could be used incombination with suitable anti-inflammatory agents. Examples of suitableanti-inflammatory agents for use in combination with the compounds ofthe present invention include prednisone, dexamethasone, cyclooxygenaseinhibitors (i.e., COX-1 and/or COX-2 inhibitors such as NSAIDs, aspirin,indomethacin, ibuprofen, piroxicam, Naproxen®, Celebrex®, Vioxx®),CTLA4-Ig agonists/antagonists, CD40 ligand antagonists, IMPDHinhibitors, such as mycophenolate (CellCept®), integrin antagonists,alpha-4 beta-7 integrin antagonists, cell adhesion inhibitors,interferon gamma antagonists, ICAM-1, tumor necrosis factor (TNF)antagonists (e.g., infliximab, OR1384, including TNF-alpha inhibitors,such as tenidap, anti-TNF antibodies or soluble TNF receptor such asetanercept (Enbrel®), rapamycin (sirolimus or Rapamune) and leflunomide(Arava)), prostaglandin synthesis inhibitors, budesonide, clofazimine,CNI-1493, CD4 antagonists (e.g., priliximab), p38 mitogen-activatedprotein kinase inhibitors, protein tyrosine kinase (PTK) inhibitors, IKKinhibitors, and therapies for the treatment of irritable bowel syndrome(e.g., Zelnorm® and Maxi-K® openers such as those disclosed in U.S. Pat.No. 6,184,231 B1).

Exemplary of such other therapeutic agents which may be used incombination with cannabinoid receptor modulators include the following:cyclosporins (e.g., cyclosporin A), anti-IL-2 receptor (Anti-Tac),anti-CD45RB, anti-CD2, anti-CD3 (OKT-3), anti-CD4, anti-CD80, anti-CD86,monoclonal antibody OKT3, agents blocking the interaction between CD40and gp39, such as antibodies specific for CD40 and/or gp39 (i.e.,CD154), fusion proteins constructed from CD40 and gp39 (CD40Ig andCD8gp39), inhibitors, such as nuclear translocation inhibitors, ofNF-kappa B function, such as deoxyspergualin (DSG), gold compounds,antiproliferative agents such as methotrexate, FK506 (tacrolimus,Prograf), mycophenolate mofetil, cytotoxic drugs such as azathiprine andcyclophosphamide, anticytokines such as antiIL-4 or IL-4 receptor fusionproteins and PDE 4 inhibitors such as Ariflo, and the PTK inhibitorsdisclosed in the following U.S. patent applications, incorporated hereinby reference in their entirety: Ser. No. 09/097,338, filed Jun. 15,1998; Ser. No. 09/094,797, filed Jun. 15, 1998; Ser. No. 09/173,413,filed Oct. 15, 1998; and Ser. No. 09/262,525, filed Mar. 4, 1999. Seealso the following documents and references cited therein andincorporated herein by reference: Hollenbaugh, D., et al., “CleavableCD4OIg Fusion Proteins and the Binding to Sgp39”, J Immunol. Methods(Netherlands), 188 (1), pp. 1-7 (Dec. 15, 1995); Hollenbaugh, D., etal., “The Human T Cell Antigen Gp39, A Member of the TNF Gene Family, Isa Ligand for the CD40 Receptor: Expression of a Soluble Form of Gp39with B Cell Co-Stimulatory Activity”, EMBO J(England), 11 (12), pp.4313-4321 (December 1992); and Moreland, L. W. et al., “Treatment ofRheumatoid Arthritis with a Recombinant Human Tumor Necrosis FactorReceptor (P75)-Fc Fusion Protein, ”New England J. of Medicine, 337 (3),pp. 141-147 (1997).

The above other therapeutic agents, when employed in combination withthe compounds of the present invention, may be used, for example, inthose amounts indicated in the Physicians' Desk Reference (PDR) or asotherwise determined by one of ordinary skill in the art.

The compounds of formula (I) of the invention can be administered orallyor parenterally, such as subcutaneously or intravenously, as well as bynasal application, rectally or sublingually to various mammalian speciesknown to be subject to such maladies, e.g., humans, in an effectiveamount up to 1 gram, preferably up to 200 mg, more preferably up to 100mg in a regimen of single, two or four divided daily doses.

The compounds of the formula (I) can be administered for any of the usesdescribed herein by any suitable means, for example, orally, such as inthe form of tablets, capsules, granules or powders; sublingually;bucally; parenterally, such as by subcutaneous, intravenous,intramuscular, or intrastemal injection or infusion techniques (e.g., assterile injectable aqueous or non-aqueous solutions or suspensions);nasally, including administration to the nasal membranes, such as byinhalation spray; topically, such as in the form of a cream or ointment;or rectally such as in the form of suppositories; in dosage unitformulations containing non-toxic, pharmaceutically acceptable vehiclesor diluents. The present compounds can, for example, be administered ina form suitable for immediate release or extended release. Immediaterelease or extended release can be achieved by the use of suitablepharmaceutical compositions comprising the present compounds, or,particularly in the case of extended release, by the use of devices suchas subcutaneous implants or osmotic pumps. The present compounds canalso be administered liposomally.

Exemplary compositions for oral administration include suspensions whichcan contain, for example, microcrystalline cellulose for imparting bulk,alginic acid or sodium alginate as a suspending agent, methylcelluloseas a viscosity enhancer, and sweeteners or flavoring agents such asthose known in the art; and immediate release tablets which can contain,for example, microcrystalline cellulose, dicalcium phosphate, starch,magnesium stearate and/or lactose and/or other excipients, binders,extenders, disintegrants, diluents and lubricants such as those known inthe art. The compounds of formula I can also be delivered through theoral cavity by sublingual and/or buccal administration. Molded tablets,compressed tablets or freeze-dried tablets are exemplary forms which maybe used. Exemplary compositions include those formulating the presentcompound(s) with fast dissolving diluents such as mannitol, lactose,sucrose and/or cyclodextrins. Also included in such formulations may behigh molecular weight excipients such as celluloses (avicel) orpolyethylene glycols (PEG). Such formulations can also include anexcipient to aid mucosal adhesion such as hydroxy propyl cellulose(HPC), hydroxy propyl methyl cellulose (HPMC), sodium carboxy methylcellulose (SCMC), maleic anhydride copolymer (e.g., Gantrez), and agentsto control release such as polyacrylic copolymer (e.g. Carbopol 934).Lubricants, glidants, flavors, coloring agents and stabilizers may alsobe added for ease of fabrication and use.

Exemplary compositions for nasal aerosol or inhalation administrationinclude solutions in saline which can contain, for example, benzylalcohol or other suitable preservatives, absorption promoters to enhancebioavailability, and/or other solubilizing or dispersing agents such asthose known in the art.

Exemplary compositions for parenteral administration include injectablesolutions or suspensions which can contain, for example, suitablenon-toxic, parenterally acceptable diluents or solvents, such asmannitol, 1,3-butanediol, water, Ringer's solution, an isotonic sodiumchloride solution, or other suitable dispersing or wetting andsuspending agents, including synthetic mono- or diglycerides, and fattyacids, including oleic acid, or Cremaphor.

Exemplary compositions for rectal administration include suppositorieswhich can contain, for example, a suitable non-irritating excipient,such as cocoa butter, synthetic glyceride esters or polyethyleneglycols, which are solid at ordinary temperatures, but liquify and/ordissolve in the rectal cavity to release the drug.

Exemplary compositions for topical administration include a topicalcarrier such as Plastibase (mineral oil gelled with polyethylene).

It will be understood that the specific dose level and frequency ofdosage for any particular subject can be varied and will depend upon avariety of factors including the activity of the specific compoundemployed, the metabolic stability and length of action of that compound,the species, age, body weight, general health, sex and diet of thesubject, the mode and time of administration, rate of excretion, drugcombination, and severity of the particular condition.

It should be understood that while this invention has been describedherein in terms of specific embodiments set forth in detail, suchembodiments are presented by way of illustration of the generalprinciples of the invention, and the invention is not necessarilylimited thereto. Certain modifications and variations in any givenmaterial, process step or chemical formula will be readily apparent tothose skilled in the art without departing from the true spirit andscope of the present invention, and all such modifications andvariations should be considered within the scope of the claims thatfollow.

1. A compound or a prodrug or a solvate or a pharmaceutically acceptablesalt or a stereoisomer thereof according to Formula I

wherein: A is selected from the group consisting of N and CR^(3a); B isselected from the group consisting of a direct bond, oxygen, sulfur,NR⁶, C(O), C(O)O, OC(O), OC(O)O, C(O)NR⁶, NR⁶C(O), NR⁶C(O)O, S(O),S(O)₂, S(O)NR⁶, S(O)₂NR⁶, NR⁶S(O), NR⁶S(O)₂, and NR⁶C(O)NR⁷; R¹ and R²are independently selected from the group consisting of aryl substitutedwith 1 to 5 R⁴ and heteroaryl optionally substituted with 1 to 4 R⁴;when both R¹ and R² are heteroaryl, then either R¹ or R² is substitutedwith at least one R⁴; R³ and R^(3a) are independently selected from thegroup consisting of hydrogen, halogen, CF₃, OCHF₂, OCF₃, CN, NO₂, OCH₃,SCH₃, OR⁵, SR⁵, NR⁵R⁶, C(O)H, C(O)R⁵, C(O)NR⁵R⁶, NR⁶C(O)R⁵, C(O)OR⁵,OC(O)R⁵, OC(O)OR⁵, S(O)R⁵, S(O)₂R⁵, S(O)NR⁵R⁶, S(O)₂NR⁵R⁶, NR6S(O)R⁵,NR⁶S(O)₂R⁵, NR⁶C(O)R⁵ NR⁶C(O)OR₅, NR⁶S(O)₂R⁵, NR⁶C(O)NR⁷R⁵, alkyl,alkenyl, alkynyl, cycloalkyl and heterocyclyl, any of which may beoptionally substituted with 1 to 6 R⁹; R⁴, at each occurrence, isindependently selected from the group consisting of halogen, OH, CF₃,OCHF₂, OCF₃, CN, No₂, OCH₃, SCH₃, OR⁵, SR⁵, NR⁵R⁶, C(O)H, C(O)R⁵,C(O)NR⁵R⁶, NR⁶C(O)R⁵, C(O)OR⁵, OC(O)R⁵, OC(O)OR⁵, S(O)R⁵, S(O)₂R⁵,S(O)NR⁵R⁶, S(O)₂NR⁵R⁶, NR⁶S(O)R⁵, NR⁶S(O)₂R⁵, NR⁶ C(O)R⁵, NR⁶C(O)OR⁵,NR⁶S(O)₂R⁵, NR ⁶C(O)NR⁵R⁷, alkyl, alkenyl, alkynyl, cycloalkyl,heterocyclyl, aryl and heteroaryl, any of which may be optionallysubstituted with 1 to 6 R⁹; R⁵ is selected from the group consisting ofC₁₋₄ alkyl optionally substituted with 1 to 3 R⁹, C₂₋₄ alkenyloptionally substituted with 1 to 2 R⁹, C₂₋₄ alkynyl optionallysubstituted with 1 to 2 R⁹, C₃₋₁₀cycloalkyl optionally substituted with1 to 6 R¹⁰, C₃₋₁₀ heterocyclyl optionally substituted with 1 to 6 R¹⁰,aryl optionally substituted with 1 to 5 R¹¹ and heteroaryl optionallysubstituted with 1 to 3 R ¹⁰; R⁶ and R⁷ are independently is selectedfrom the group consisting of hydrogen, C₁₋₄ alkyl optionally substitutedwith 1 to 3 R⁹, C₂₋₄ alkenyl optionally substituted with 1 to 2 R⁹, C₂₋₄alkynyl optionally substituted with 1 to 2 R⁹, C₃₋₆ cycloalkyloptionally substituted with 1 to 3 R¹⁰, and C₃₋₆ heterocyclyl optionallysubstituted with 1 to3R¹⁰; alternatively, R⁵ and R⁶join to form a 3 to7-membered ring optionally substituted with oxygen or NR¹²;alternatively, R⁵ and R⁶ when attached to N may be combined to form a 5to 10-membered bicyclic heterocyclic ring system containing from 1 to 3heteroatoms selected from the group consisting of nitrogen, oxygen, andsulfur, wherein said bicyclic heterocyclic ring system is unsaturated orpartially saturated, wherein said bicyclic heterocyclic ring system isoptionally substituted with 1 to 3 R¹³; alternatively, R⁶ and R⁷ join toform a 5 to 7-membered ring optionally substituted with oxygen or NR¹²;alternatively, R⁶ and R⁷ when attached to N may be combined to form a 9-or 10-membered bicyclic heterocyclic ring system containing from 1 to 3heteroatoms selected from the group consisting of nitrogen, oxygen, andsulfur, wherein said bicyclic heterocyclic ring system is unsaturated orpartially saturated, wherein said bicyclic heterocyclic ring system isoptionally substituted with 1 to 3 R¹³; R⁸ is selected from the groupconsisting of alkyl optionally substituted with 1 to 6 R⁹, alkenyloptionally substituted with 1 to 6 R⁹, alkynyl optionally substitutedwith 1 to 6 R⁹, cycloalkyl optionally substituted with 1 to 6 R¹⁰,heterocyclyl optionally substituted with 1 to 6 R¹⁰, aryl optionallysubstituted with 1 to 5 R⁴, heteroaryl optionally substituted with 1 to3 R⁴; R⁹, at each occurrence, is independently selected from the groupconsisting of halogen, OH, CF₃, OCHF₂, OCF₃, CN, NO₂, OCH₃, SCH₃, OR¹²,SR ¹², NR¹²R^(12a), C(O)H, C(O)R¹², C(O)NR¹²R^(12a), NR¹²C(O)R^(12a),C(O)OR¹², OC(O)R¹², OC(O)OR¹², S(O)R¹², S(O)₂R¹², S(O)NR¹²R ^(12a),S(O)₂NR¹²R^(12a), NR¹²S(O)R^(12a), NR¹²S(O)₂R^(12a), NR¹²C(O)R^(12a),NR¹²C(O)OR^(12a), NR¹²S(O)₂R^(12a), C₁₋₃ haloalkyl, C₁₋₄ alkoxy, C₃₋₆cycloalkyl optionally substituted with 1 to 3 R¹⁰, C₃₋₁₀ heterocyclyloptional substituted with 1 to 3 R¹⁰, substituted with 1 to 5 R¹¹ andheteroaryl optionally substituted with 1 to 3 R¹⁰; R¹⁰, at eachoccurrence, is independently selected from the group consisting of ═O,halogen, OH, CF₃, OCHF₂, OCF₃, CN, NO₂, OCH₃, SCH₃, OR¹², SR¹²,NR¹²R^(12a), C(O)H, C(O)R¹², C(O)NR¹²R^(12a), NR¹²C(O)R^(12a), C(O)OR¹²,OC(O)R¹², OC(O)OR¹²,S(O)R¹²,S(O)₂R¹², S(O)NR¹²R^(12a),S(O)₂NR¹²R^(12a),NR¹²S(O)R^(12a), NR¹²S(O)₂R^(12a), NR¹²C(O)R^(12a), NR¹²C(O)OR^(12a),NR¹²S(O)₂R^(12a), C₁₋₄ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₄ alkoxyand C₁₋₄ haloalkyl; R¹¹, at each occurrence, is independently selectedfrom the group consisting of halogen, OH, CF₃, OCHF₂, OCF₃, CN, NO₂,OCH₃, SCH₃, C₁₋₄ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₄ alkoxy and C₁₋₄haloalkyl; R¹² and R^(12a), at each occurrence, are independentlyselected from the group consisting of H and C₁₋₄ alkyl; R¹³, at eachoccurrence, is independently selected from the group consisting of H,OH, halogen, CN, NO₂, CF₃, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄haloalkyl and C₁₋₃ alkoxy.
 2. The compound according to claim 1, whereinR³ and R^(3a) are independently selected from the group consisting ofhydrogen, halogen, CF₃, OCHF₂, OCF₃, CN, OCH₃, SCH₃, C₁₋₄ alkyl.
 3. Thecompound according to claim 1, wherein B is selected from the groupconsisting of a direct bond, oxygen, sulfur, NR⁶, C(O), C(O)NR⁶.
 4. Thecompound according to claim 1, wherein R⁸ is selected from the groupconsisting of C₁₋₆ alkyl optionally substituted with 1 to 4 R⁹, C₂₋₆alkenyl optionally substituted with 1 to 4 R⁹, C₂₋₆ alkynyl optionallysubstituted with 1 to 4 R⁹, C₃₋₈ cycloalkyl optionally substituted with1 to 4 R¹⁰; 3-6 membered heterocyclyl optionally substituted with 1 to 3R¹⁰, aryl optionally substituted with 1 to 3 R⁴, 5-10 memberedheteroaryl optionally substituted with 1 to 3 R⁴.
 5. The compoundaccording to claim 1, wherein R⁴, at each occurrence, is independentlyselected from the group consisting of halogen OH, CF₃, OCHF₂, OCF₃, CN,NO₂, OCH₃, SCH₃, OR⁵, SR⁵, NR⁵R⁶, S(O)R⁵, S(O)₂R⁵, S(O)₂NR⁵R⁶, C₁₋₄alkyl, C₃₋₆ cycloalkyl, 3-6 membered heterocyclyl, any of which may beoptionally substituted with 1 to 6 R⁹; R⁵ and R⁶ are independentlyselected from the group consisting of methyl, ethyl, n-propyl, i-propyland cyclopropyl; alternatively, R⁵ and R⁶join to form a 3-6-memberedring optionally substituted with oxygen or NR¹²; R⁹, at each occurrence,is independently selected from the group consisting of halogen, OH, CF₃,OCHF₂, OCF₃, CN, OCH₃ and N(CH₃)₂; R¹² and R^(12a), at each occurrence,are independently selected from the group consisting of H ,methyl andethyl.
 6. The compound according to claim 1, wherein R⁸ is selected fromthe group consisting of C₁₋₄ alkyl optionally substituted with 1 to 4R⁹, C₃₋₈ cycloalkyl optionally substituted with 1 to 4 R¹⁰; 3-6 memberedheterocyclyl substituted with 0 to 3 R¹⁰, aryl optionally substitutedwith 1 to 3 R⁴, 5-10 membered heteroaryl optionally substituted with 1to 3 R⁴; R⁴, at each occurrence, is independently selected from thegroup consisting of halogen OH, CF₃, OCHF₂, OCF₃, CN, NO₂, OCH₃, SCH₃,N(CH₃)₂, methyl, ethyl, n-propyl, i-propyl and cyclopropyl; R¹⁰, at eachoccurrence, is independently selected from the group consisting of ═O,halogen, OH, CF₃, OCHF₂, OCF₃, CN, NO₂, OCH₃, SCH₃, methyl, ethyl,n-propyl, i-propyl and cyclopropyl, NR¹²R^(12a), C(O)NR¹²R^(12a),C(O)OR¹².
 7. The compound according to claim 1, wherein R³ and R^(3a)are independently selected from the group consisting of hydrogen andmethyl.
 8. The compound according to claim 1, wherein R¹ is selectedfrom the group consisting of 2-halo-phenyl, 2-(C₁₋₃)alkyl-phenyl,2-(C₁₋₃)alkoxy-phenyl, 2-CF₃-phenyl, 2-CN-phenyl, 2-halo-4-pyridyl,2-(C₁₋₃)alkyl-4-pyridyl, 2-(C₁₋₃)alkoxy-4-pyridyl, 2-CF₃-4-pyridyl,2-CN-4-pyridyl, 2-halo-4-halophenyl, 2-(C₁₋₃)alkyl-4-halo-phenyl,2-(C₁₋₃)alkoxy-4-halo-phenyl, 2-CF₃-4-halo-phenyl, 2-CN-4-halo-phenyl,2-halo-4-(C₁₋₃)alkyl-phenyl, 2-(C₁₋₃)alkyl-4-(C₁₋₃)alkyl-phenyl,2-(C₁₋₃)alkoxy-4-(C₁₋₃)alkyl-phenyl, 2-CF₃-4-(C₁₋₃)alkyl-phenyl,2-CN-4-(C₁₋₃)alkyl-phenyl, 2-halo-4-(C₁₋₃)alkyl-phenyl,2-(C₁₋₃)alkyl-4-(C₁₋₃)alkoxy-phenyl,2-(C₁₋₃)alkoxy-4-(C₁₋₃)alkoxy-phenyl, 2-CF₃-4-(C₁₋₃)alkoxy-phenyl,2-CN-4-(C₁₋₃)alkoxy-phenyl, 2halo-4-CF₃-phenyl,2-(C₁₋₃)alkyl-4-CF₃-phenyl, 2-(C₁₋₃)alkoxy-4-CF₃-phenyl,2-halo-4-CN-phenyl, 2-(C₁₋₃)alkyl-4-CN-phenyl and2-(C₁₋₃)alkoxy-4-CN-phenyl.
 9. The compounds according to claim 1,wherein the compounds are selected from the group consisting of:


10. The compounds according to claim 1, wherein the compounds areselected from the group consisting of:


11. A pharmaceutical composition, comprising: at least one compoundaccording to claim 1; and at least one pharmaceutically acceptablecarrier or diluent. 12 The pharmaceutical composition according to claim11 further comprising: at least one additional therapeutic agent. 13 Apharmaceutical combination comprising a pharmaceutical composition ofclaim 11 and a therapeutic agent selected from the group consisting ofanti-obesity agents; appetite suppressants; anti-diabetic agents;anti-hyperlipidemia agents; hypolipidemic agents; hypocholesterolemicagents; lipid-modulating agents; cholesterol-lowering agents;lipid-lowering agents; HDL-raising agent, anti-hypertensive agents;agents used to treat sleep disorders; agents used to treat substanceabuse and addictive disorders; anti-anxiety agents; anti-depressants;anti-psychotic agents; cognition enhancing agents; agents used to treatcognitive disorders; agents used to treat Alzheimer's disease; agentsused to treat Parkinson's disease; anti-inflammatory agents; agents usedto treat neurodegeneration; agents used to treat arteriosclerosis;agents used to treat respiratory conditions; agents used to treat boweldisorders; cardiac glycosides; and anti-tumor agents.
 14. Thepharmaceutical combination according to claim 13 wherein the othertherapeutic agent may be administered prior to, simultaneously with, orfollowing the administration of the pharmaceutical composition of claim11.
 15. A method for treating obesity, comprising: administering atherapeutically effective amount of at least one cannabinoid receptor 1antagonist according to claim 1 to a patient in need.
 16. A method forsmoking cessation, comprising: administering a therapeutically effectiveamount of at least one cannabinoid receptor 1 antagonist according toclaim 1 to a patient in need.